U.S. patent number 8,076,376 [Application Number 11/490,143] was granted by the patent office on 2011-12-13 for aniline sulfonamide derivatives and their uses.
Invention is credited to Xiao He, Dustin McMinn, Jay P. Powers, Yosup Rew, Daqing Sun.
United States Patent |
8,076,376 |
Powers , et al. |
December 13, 2011 |
Aniline sulfonamide derivatives and their uses
Abstract
Aniline sulfonamide derivatives according to formula I have
therapeutic utility, particularly in the treatment of diabetes,
obesity and related conditions and disorders: ##STR00001## where
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and L are set
forth in the description.
Inventors: |
Powers; Jay P. (Pacifica,
CA), He; Xiao (Foster City, CA), McMinn; Dustin
(Pacifica, CA), Rew; Yosup (Foster City, CA), Sun;
Daqing (Forest City, CA) |
Family
ID: |
37075930 |
Appl.
No.: |
11/490,143 |
Filed: |
July 21, 2006 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20070021502 A1 |
Jan 25, 2007 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
60701476 |
Jul 22, 2005 |
|
|
|
|
Current U.S.
Class: |
514/604;
564/92 |
Current CPC
Class: |
A61P
3/06 (20180101); A61P 15/08 (20180101); A61P
17/06 (20180101); A61P 37/00 (20180101); A61P
9/10 (20180101); A61P 29/00 (20180101); A61P
35/00 (20180101); A61P 43/00 (20180101); A61P
9/12 (20180101); A61P 13/12 (20180101); A61P
3/04 (20180101); A61P 27/02 (20180101); A61P
25/24 (20180101); A61P 3/10 (20180101); A61P
9/00 (20180101); C07C 311/21 (20130101); C07C
311/44 (20130101); A61P 27/06 (20180101); A61P
31/12 (20180101); C07C 2601/04 (20170501); C07C
2601/02 (20170501) |
Current International
Class: |
A61K
31/18 (20060101); C07C 311/37 (20060101) |
Field of
Search: |
;514/604 ;564/92 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2377999 AA |
|
Jan 2001 |
|
CA |
|
2438133 AA |
|
Aug 2002 |
|
CA |
|
2003267969 |
|
Sep 2003 |
|
JP |
|
2004500332 |
|
Jan 2004 |
|
JP |
|
2004524027 |
|
Aug 2004 |
|
JP |
|
2004533216 |
|
Nov 2004 |
|
JP |
|
WO0054759 |
|
Sep 2000 |
|
WO |
|
WO 01/03705 |
|
Jan 2001 |
|
WO |
|
WO01/70816 |
|
Sep 2001 |
|
WO |
|
WO 01/82917 |
|
Nov 2001 |
|
WO |
|
WO 02/066612 |
|
Aug 2002 |
|
WO |
|
WO 02/066615 |
|
Aug 2002 |
|
WO |
|
WO03/049685 |
|
Jun 2003 |
|
WO |
|
WO03063576 |
|
Aug 2003 |
|
WO |
|
WO03082198 |
|
Oct 2003 |
|
WO |
|
WO2004058175 |
|
Jul 2004 |
|
WO |
|
WO2004058819 |
|
Jul 2004 |
|
WO |
|
WO 2004/065351 |
|
Aug 2004 |
|
WO |
|
WO 2004/089896 |
|
Oct 2004 |
|
WO |
|
WO2004098506 |
|
Nov 2004 |
|
WO |
|
WO2004101776 |
|
Nov 2004 |
|
WO |
|
WO2004104224 |
|
Dec 2004 |
|
WO |
|
Other References
International Search Report for PCT Application No.
PCT/US2006/028059 mailed on Nov. 13, 2006. cited by other .
Li, Leping, et al., Discovery and Optimization of a novel series of
liver X receptor-agonists, Bioorganic & Medicinal Chemistry
Letters 16 (2006) 1638-1642. cited by other .
Stein, et al., LXR Activation and Cholesterol Efflux from a
Lipoprotein Depot in vivo, Biochimica et Biophysica Acta (2004),
vol. 1686 (1-2), pp. 24-29. cited by other .
Fukuchi, et al., Antiproliferative Effect of Liver X Receptor
Agonists on LNCaP Human Prostate Cancer Cells, Cancer Research
(2004), vol. 64(21), pp. 7686-7689. cited by other .
Jakel, et al., The Liver X Receptor Ligand T0901317 Down-regulates
APOA5 Gene Expression through Activation of SREBP-1c, Journal of
Biological Chemistry (2004), vol. 279(44), pp. 45462-45469. cited
by other .
Quinet, et al., Gene-selective Modulation by a Synthetic Oxysterol
Ligand of the Liver X Receptor, Journal of Lipid Research, (2004),
vol. 45(10), pp. 1929-1942. cited by other .
Houck, et al., T0901317 is a Dual LXR/FXR Agonist, Molcular
Genetics and Metabolism, (2004), vol. 83(1/2), pp. 184-187. cited
by other .
Miao, et al., Raising HDL Cholesterol Without Inducing Hepatic
Steatosis and Hypertriglyceridemia by a Selective LXR Modulator,
Journal of Lipid Research, (2004), vol. 45(8), pp. 1410-1417. cited
by other .
Liang, et al., Liver X Receptors (LXRs) Regulate Apolipoprotein
AIV-Implications of the Antiatherosclerotic Effect of LXR Agonists,
Molecular Endocrinology, (2004), vol. 18(8), pp. 2000-2010. cited
by other .
Schmuth, et al., The Effect of LXR Activators on AP-1 Proteins in
Keratinocytes, Journal of Investigative Dermatology, (2004), vol.
123(1), pp. 41-48. cited by other .
Beyer, et al., Coadministration of a Liver X Receptor Agonist and a
Peroxisome Proliferator Activator Receptor-.alpha. Agonist in Mice:
Effects of Nuclear Receptor Interplay on High-Denisty Lipoprotein
and Triglyceride Metabolism in Vivo, Journal of Pharmacology and
Experimental Therapeutics, (2004), vol. 309(3), pp. 861-868. cited
by other .
Toresson, et al., Purification of Functional Full-Length Liver X
Receptor .beta. Produced in Escherichia coli, Protein Expression
and Purification, (2004), vol. 35(2), pp. 190-198. cited by other
.
Seo, et al., Activated Liver X Receptors Stimulate Adipocyte
Differentiation Through Induction of Peroxisome
Proliferator-Activated Receptor .gamma. Expression, Molecular and
Cellular Biology, (2004), vol. 24(8), pp. 3430-3444. cited by other
.
Masson, et al., Cholesteryl Ester Transfer Protein Modulates the
Effect of Liver X Receptor Agonists on Cholesterol Transport and
Excretion in the Mouse, Journal of Lipid Research, (2004), vol.
45(3), pp. 543-550. cited by other .
Liang, et al., A Liver X Receptor and Retinoid X Receptor
Heterodimer Mediates Apolipoprotein E Expression, Secretion and
Cholesterol Homeostasis in Astrocytes, Journal of Neurochemistry,
(2004), vol. 88(3), pp. 623-634. cited by other .
Chisholm, et al., The LXr Ligand T0901317 Induces Severe
Lipogenesis in the db/db Diabetic Mouse, Journal of Lipid Research,
(2003), vol. 44(11), pp. 2039-2048. cited by other .
Hoerer, et al., Crystal Structure of the Human Liver X Receptor
.beta. Ligand-Binding Domain in Complex with a Synthetic Agonist,
Journal of Molecular Biology, (2003), vol. 334(5), pp. 853-861.
cited by other .
Rowe, et al., Enhanced Synthesis of the Oxysterol 24(S),
25-Epoxycholesterol in Macrophages by Inhibitors of
2,3-Oxidosqualene: Lanosterol Cyclase, Circulation Research,
(2003), vol. 93(8), pp. 717-725. cited by other .
Faernegardh, et al., The Three-Dimensional Structure of the Liver X
Receptor .beta. Reveals a Flexible Ligand-Binding Pocket That Can
Accommodate Fundamentally Different Ligands, Journal of Biological
Chemistry, (2003), vol. 278(40), pp. 38821-38828. cited by other
.
Svensson, et al., Crystal Structure of the Heterodimeric Complex of
LXR.alpha. and Rxr.beta. Ligand-Binding Domains in a Fully
Agonistic Conformation, EMBO Journal, (2003), vol. 22(18), pp.
4625-4633. cited by other .
Kaneko, et al., Induction of Intestinal ATP-Binding Cassette
Transporters by a Phytosterol-Derived Liver X Receptor Agonist,
Journal of Biological Chemistry, (2003), vol. 278(38), pp.
36091-36098. cited by other .
Miyazaki, et al., Identification and Characterization of Murine
SCD4, a Novel Heart-Specific Stearoyl-CoA Desaturase lsoforrn
Regulated by Leptin and Dietary Factors, Journal of Biological
Chemistry, (2003), vol. 278(36), pp. 33904-33911. cited by other
.
Wang, et al., Molecular Determinants of LXR.alpha. Agonism, Journal
of Molecular Graphics & Modelling, (2003), vol. 22(2), pp.
173-181. cited by other .
Williams, et al., X-ray Crystal Structure of the Liver X Receptor
.beta. Ligand Binding Domain: Regulation by a Histidine-Tryptophan
Switch, Journal of Biological Chemistry, (2003), vol. 278(29), pp.
27138-27143. cited by other .
Yoshikawa, et al., Cross-Talk Between Peroxisome
Proliferator-Activated Receptor (PPAR) .alpha. and Liver X Receptor
(LXR) in Nutritional Regulation of Fatty Acid Metabolism. I. PPARs
Suppress Sterol Regulatory Element Binding Protein-1c Promoter
Through Inhibition of LXR Signaling, Molecular Endocrinology,
(2003), vol. 17(7), pp. 1240-1254. cited by other .
Perez, et al., Expression of Nuclear Receptors and Apo E Secretion
During the Differentiation of Monocytic THP-1 Cells Into
Macrophages, Cell Biology and Toxicology, (2003), vol. 19(2), pp.
95-105. cited by other .
Goodwin, et al., Differential Regulation of Rat and Human CYP7A1 by
the Nuclear Oxysterol Receptor Liver X Receptor-.alpha., Molecular
Endocrinology, (2003), vol. 17(3), pp. 386-394. cited by other
.
Juvet, et al., On the Role of Liver X Receptors in Lipid
Accumulation in Adipocytes, Molecular Endocrinology, (2003), vol.
17(2), pp. 172-182. cited by other .
Terasaka, et al., T-0901317, a Synthetic Liver X Receptor Ligand,
Inhibits Development of Atherosclerosis in LDL Receptor-Deficient
Mice, FEBS Letters, (2003), vol. 536(1-3), pp. 6-11. cited by other
.
Kaplan, et al., Regulation of the Angiopoietin-Like Protein 3 Gene
by LXR, Journal of Lipid Research, (2003), vol. 44(1), pp. 136-143.
cited by other .
Cao, et al., Antidiabetic Action of a Liver X Receptor Agonist
Mediated by Inhibition of Hepatic Gluconeogenesis, Journal of
Biological Chemistry, (2003), vol. 278(2), pp. 1131-1136. cited by
other .
Brendel, et al., The Small Heterodimer Partner Interacts With the
Liver X Receptor .alpha. and Represses its Transcriptional
Activity, Molecular Endocrinology, (2002), vol. 16(9), pp.
2065-2076. cited by other .
Stulnig, et al., Liver X Receptors Downregulate
11.beta.-hydroxysteroid Dehydrogenase Type 1 Expression and
Activity, Diabetes, (2002), vol. 51(8), pp. 2426-2433. cited by
other .
Murthy, et al., LXR/RXR Activation Enhances Basolateral Efflux of
Cholesterol in CaCo-2 Cells, Journal of Lipid Research, (2002),
vol. 43(7), pp. 1054-1064. cited by other .
Collins, et al., Identification of a Nonsteroidal Liver X Receptor
Agonist Through Parallel Array Synthesis of Tertiary Amines,
Journal of Medicinal Chemistry, (2002), vol. 45(10), pp. 1963-1966.
cited by other .
Song, et al., Hypolipidemic Effects of Selective Liver X Receptor
Alpha Agonists, Steroids, (2001), vol. 66(9), pp. 673-681. cited by
other .
Schultz, et al., Role of LXRs in Control of Lipogenesis, Genes
& Development, (2000), vol. 14(22), pp. 2831-2838. cited by
other.
|
Primary Examiner: Sullivan; Peter O
Attorney, Agent or Firm: Lemoine; Elsa D.
Claims
We claim:
1. A compound having the formula (I): ##STR00071## or a
pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R.sup.1, R.sup.2, and R.sup.3, together with the carbon atom to
which they are attached, are an (S)-trifluoromethyl carbinol group
of the formula: ##STR00072## or an (R)-trifluoromethyl carbinol
group of the formula: ##STR00073## R.sup.4 is a member selected
from the group consisting of hydrogen, halogen,
(C.sub.1-C.sub.8)alkyl and (C.sub.3-C.sub.8)cycloalkyl; R.sup.5 is
selected from the group consisting of hydrogen, --OH, halogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)heteroalkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)heterocycloalkyl, C(O)R', C(O)NR'.sub.2,
NR'.sub.2, NR'C(O)R', CN, NO.sub.2, aryl, and heteroaryl; R.sup.6
is aryl or heteroaryl, or R.sup.6 optionally may be combined with
R.sup.5 to form a 5- to 6-membered fused ring containing L, the
nitrogen atom to which L is attached, and the sulfur atom to which
R.sup.6 is attached; L is selected from the group consisting of a
direct bond, (C.sub.1-C.sub.4)alkylene and
(C.sub.2-C.sub.4)alkenylene; wherein any cycloalkyl portion,
heterocycloalkyl portion, aryl or heteroaryl portion is optionally
substituted with from one to four members selected from the group
consisting of halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)hydroxyalkyl, --C(O)R', --C(O)OR', --NR'C(O)OR'',
--OR', --SR', --OC(O)R', --C(O)N(R').sub.2, --S(O)R'',
--SO.sub.2R'', --SO.sub.2N(R').sub.2, --N(R').sub.2 and
--NR'C(O)R'; wherein each occurrence of R' is independently H or an
unsubstituted member selected from the group consisting of
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)heterocycloalkyl,
heteroaryl, aryl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8) heterocycloalkyl(C.sub.1-C.sub.6)alkyl,
heteroaryl(C.sub.1-C.sub.6)alkyl, and aryl(C.sub.1-C.sub.6)alkyl,
wherein two R' groups, when attached to the same nitrogen atom, can
be combined with the nitrogen atom to which they are attached to
form a heterocycle or heteroaryl group; and wherein each occurrence
of R'' is independently an unsubstituted member selected from the
group consisting of (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)heterocycloalkyl,
heteroaryl, aryl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkyl,
heteroaryl(C.sub.1-C.sub.6)alkyl and
aryl(C.sub.1-C.sub.6)alkyl.
2. The compound according to claim 1, wherein L is a direct
bond.
3. The compound according to claim 1, wherein R.sup.5 is
(C.sub.1-C.sub.8)alkyl.
4. The compound according to claim 3, wherein R.sup.5 is
(C.sub.1-C.sub.3)alkyl.
5. The compound according to claim 4, wherein R.sup.5 is selected
from the group consisting of methyl, ethyl, and isopropyl.
6. The compound according to claim 5, wherein R.sup.5 is
isopropyl.
7. The compound according to claim 1, wherein R.sup.5 is
(C.sub.3-C.sub.8)cycloalkyl.
8. The compound according to claim 7, wherein R.sup.5 is
cyclopropyl or cyclobutyl.
9. The compound according to claim 1, wherein R.sup.6 is aryl.
10. The compound according to claim 9, wherein R.sup.6 is aryl
optionally substituted with one to four substituents.
11. The compound according to claim 10, wherein R.sup.6 is
dichloro-substituted phenyl.
12. The compound according to claim 10, wherein R.sup.6 is
2-chloro-5-cyano-phenyl.
13. The compound according to claim 10, wherein R.sup.6 is
2-chloro-phenyl.
14. The compound according to claim 10, wherein R.sup.6 is
2-chloro-5-trifluoromethyl-phenyl.
15. The compound according to claim 1, wherein R.sup.5 is selected
from (C.sub.1-C.sub.8)alkyl and halo-(C.sub.1-C.sub.8)alkyl and
R.sup.6 is selected from phenyl and substituted phenyl.
16. The compound according to claim 15, wherein R.sup.5 is selected
from methyl, ethyl and isopropyl and R.sup.6 is halosubstitued
phenyl or CN-substituted phenyl.
17. The compound according to claim 1, wherein R.sup.5 is a
C.sub.3-C.sub.8 cycloalkyl moiety and R.sup.6 is selected from
phenyl and substituted phenyl.
18. The compound according to claim 17, wherein R.sup.5 is
cyclopropyl or cyclobutyl.
19. The compound according to claim 1, wherein R.sup.1, R.sup.2,
and R.sup.3, together with the carbon atom to which they are
attached, are an (S)-trifluoromethyl carbinol group of the formula:
##STR00074##
20. The compound according to claim 1, wherein R.sup.1, R.sup.2,
and R.sup.3, together with the carbon atom to which they are
attached, are an (R)-trifluoromethyl carbinol group of the formula:
##STR00075##
21. A pharmaceutical composition comprising a compound according to
claim 1, and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition comprising the compound according
to claim 1, and an additional therapeutic agent.
23. A compound selected from the group consisting of:
N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzenesulf-
onamide;
2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide;
2,3-dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pheny-
l]benzenesulfonamide;
2-fluoro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]be-
nzenesulfonamide;
2,6-dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pheny-
l]benzenesulfonamide;
2-chloro-4-cyano-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide;
2,5-dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pheny-
l]benzenesulfonamide;
tert-butyl-2,5-dichloro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl-
]benzenesulfonamide;
2-chloro-N-(cyclopropylmethyl)-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl-
)phenyl]benzenesulfonamide;
2,5-dichloro-N-isobutyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl-
]benzenesulfonamide;
2-chloro-N-isopropyl-5-nitro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide;
5-amino-2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide;
5-bromo-2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide;
2-chloro-N-ethyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzen-
esulfonamide;
2-chloro-N-methyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benze-
nesulfonamide;
2-chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N
-isopropylbenzenesulfonamide;
2-chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N
-ethylbenzenesulfonamide;
2-chloro-N-(1-fluoropropan-2-yl)-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2--
yl)pheny)benzenesulfonamide;
2,5-dichloro-N-(2,2,2-trifluoroethyl)-N-[4-(1,1,1-trifluoro-2-hydroxyprop-
an-2-yl)phenyl]benzenesulfonamide;
2,3-dichloro-N-(2,2,2-trifluoroethyl)-N-[4-(1,1,1-trifluoro-2-hydroxyprop-
an-2-yl)phenyl]benzenesulfonamide;
2-chloro-N-(2,2,2-trifluoroethyl)-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-
-yl)phenyl]benzenesulfonamide;
2,3-dichloro-N-cyclopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phe-
nyl]benzenesulfonamide;
2,5-dichloro-N-cyclobutyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen-
yl]benzenesulfonamide;
2,5-dichloro-N-phenyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]b-
enzenesulfonamide;
2-cyclopropyl-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen-
yl]benzenesulfonamide, and pharmaceutically acceptable salts,
solvates, stereoisomers, and prodrugs thereof.
Description
BACKGROUND OF THE INVENTION
This invention is generally directed to novel compounds,
compositions, and the use of either in methods for modulating
hydroxysteroid dehydrogenases, such as 11.beta.-HSD1, and for
treating or preventing diseases associated with the modulation of
hydroxysteroid dehydrogenases, such as diabetes and obesity. The
methods comprise the administration, to a patient in need thereof,
of a therapeutically effective amount of an aniline sulfonamide
derivative. Novel aniline sulfonamide derivatives or
pharmaceutically acceptable salts, solvates, stereoisomers, or
prodrugs thereof are presented herein.
Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and
activation of steroid hormone receptors by converting steroid
hormones into their inactive metabolites. For a recent review, see
Nobel et al., Eur. J. Biochem. 2001, 268:4113-4125.
There exist numerous classes of HSDs. The 11-beta-hydroxysteroid
dehydrogenases (11.beta.-HSDs) catalyze the interconversion of
active glucocorticoids (such as cortisol and corticosterone), and
their inert forms (such as cortisone and 11-dehydrocorticosterone).
The isoform 11-beta-hydroxysteroid dehydrogenase type
1(11.beta.-HSD1) is expressed in liver, adipose tissue, brain, lung
and other glucocorticoid tissue and is a potential target for
therapy directed at numerous disorders that may be ameliorated by
reduction of glucocorticoid action, such as diabetes, obesity and
age-related cognitive dysfunction. Seckl, et al., Endocrinology,
2001, 142:1371-1376.
It is well known that glucocorticoids play a central role in the
development of diabetes and that glucocorticoids enable the effect
of glucagon on the liver. Long et al., J. Exp. Med. 1936, 63:
465-490; and Houssay, Endocrinology 1942, 30: 884-892. In addition,
it has been well substantiated that 11.beta.-HSD1 plays an
important role in the regulation of local glucocorticoid effect and
of glucose production in the liver. Jamieson et al., J. Endocrinol.
2000, 165:685-692. In Walker, et al., J. Clin. Endocrinol. Metab.
1995, 80:3155-3159, it was reported that the administration of the
non-specific 11.beta.-HSD1 inhibitor carbenoxolone resulted in
improved hepatic insulin sensitivity in humans.
Furthermore, the hypothesized mechanism of action of HSDs in the
treatment of diabetes has been supported by various experiments
conducted in mice and rats. These studies showed that the mRNA
levels and activities of two key enzymes in hepatic glucose
production, phosphoenolpyruvate carboxykinase (PEPCK), and
glucose-6-phosphatase (G6Pase) were reduced upon administration of
HSD inhibitors. In addition, blood glucose levels and hepatic
glucose production were shown to be reduced in 11.beta.-HSD1
knockout mice. Additional data gathered using this murine knockout
model also confirm that inhibition of 11.beta.-HSD1 will not cause
hypoglycemia, since the basal levels of PEPCK and G6Pase are
regulated independently of glucocorticoids. Kotelevtsev et al.,
Proc. Natl. Acad. Sci. USA 1997, 94: 14924-14929.
HSDs are also believed to play a role in obesity. Obesity is an
important factor in Syndrome X as well as type II (non-insulin
dependent) diabetes, and omental fat appears to be of central
importance in the development of both of these disease, as
abdominal obesity has been linked with glucose intolerance,
hyperinsulinemia, hypertriglyceridemia, and other factors of
Syndrome X (e.g., raised blood pressure, decreased levels of HDL
and increased levels of VLDL). Montague et al., Diabetes 2000,
49:883-888, 2000. It has also been reported that inhibition of the
11.beta.-HSDs in pre-adipocytes (stromal cells) resulted in a
decreased rate of differentiation into adipocytes. This is
predicted to result in diminished expansion (possibly reduction) of
the omental fat depot, which may lead to reduced central obesity.
Bujalska et al., Lancet 1997, 349:1210-1213.
Inhibition of 11.beta.-HSD1 in mature adipocytes is expected to
attenuate secretion of the plasminogen activator inhibitor 1
(PAI-1), which is an independent cardiovascular risk factor, as
reported in Halleux et al., J. Clin. Endocrinol. Metab. 1999,
84:4097-4105. In addition, a correlation has been shown to exist
between between glucocorticoid activity and certain cardiovascular
risk factors. This suggests that a reduction of the glucocorticoid
effects would be beneficial in the treatment or prevention of
certain cardiovascular diseases. Walker et al., Hypertension 1998,
31:891-895; and Fraser et al., Hypertension 1999, 33:1364-1368.
HSDs have also been implicated in the process of appetite control
and therefore are believed to play an additional role in
weight-related disorders. It is known that adrenalectomy attenuates
the effect of fasting to increase both food intake and hypothalamic
neuropeptide Y expression. This suggests that glucocorticoids play
a role in promoting food intake and that inhibition of
11.beta.-HSD1 in the brain may increase satiety, thus resulting in
a decreased food intake. Woods et al., Science 1998,
280:1378-1383.
Another possible therapeutic effect associated with modulation of
HSDs is that which is related to various pancreatic aliments. It is
reported that inhibition of 11.beta.-HSD1 in murine pancreatic
.beta.-cells results in increased insulin secretion. Davani et al.,
J. Biol. Chem. 2000, 275:34841-34844. This follows from the
discovery that glucocorticoids were previously found to be
responsible for reduced pancreatic insulin release in vivo,
Billaudel et al., Horm. Metab. Res. 1979, 11:555-560. Thus, it is
suggested that inhibition of 11.beta.-HSD1 would yield other
beneficial effects in the treatment of diabetes other than the
predicted effects on the liver and fat reduction.
11.beta.-HSD1 also regulates glucocorticoid activity in the brain
and thus contributes to neurotoxicity. Rajan et al., Neuroscience
1996, 16:65-70; and Seckl et al., Neuroendocrinol. 2000, 18:49-99.
Stress and/or glucocorticoids are known to influence cognitive
function (de Quervain et al., Nature 1998, 394:787-790), and
unpublished results indicate significant memory improvement in rats
treated with a non-specific 11.beta.-HSD inhibitor. These reports,
in addition to the known effects of glucocorticoids in the brain,
suggest that inhibiting HSDs in the brain may have a positive
therapeutic effect against anxiety and related conditions. Tronche
et al., Nature Genetics 1999, 23:99-103. 11.beta.-HSD1 reactivates
11-DHC to corticosterone in hippocampal cells and can potentiate
kinase neurotoxicity, resulting in age-related learning
impairments. Therefore, selective inhibitors of 11.beta.-HSD1 are
believed to protect against hippocampal function decline with age.
Yau et al., Proc Natl. Acad. Sci. USA 2001, 98:4716-4721. Thus, it
has been hypothesized that inhibition of 11.beta.-HSD1 in the human
brain would protect against deleterious glucocorticoid-mediated
effects on neuronal function, such as cognitive impairment,
depression, and increased appetite.
HSDs are believed to play a role in immunomodulation based on the
general perception that glucocorticoids suppress the immune system.
There is known to be a dynamic interaction between the immune
system and the HPA (hypothalamopituitary-adrenal) axis (Rook,
Baillier's Clin. Endocrinol. Metab. 2000, 13: 576-581), and
glucocorticoids help balance between cell-mediated responses and
humoral responses. Increased glucocorticoid activity, which may be
induced by stress, is associated with a humoral response and as
such, the inhibition of 11.beta.-HSD1 may result in shifting the
response towards a cell-based reaction. In certain disease states,
such as tuberculosis, leprosy, and psoriasis, the immune reaction
is typically biased towards a humoral response when a cell-based
response might be more appropriate. Inhibition of 11.beta.-HSD1 is
being studied for use to direct a cell-based response in these
instances. Mason, Immunology Today 1991, 12:57-60. It follows then,
that an alternative utility of 11.beta.-HSD1 inhibition would be to
bolster a temporal immune response in association with immunization
to ensure that a cell based response would be obtained.
Recent reports suggest that the levels of glucocorticoid target
receptors and of HSDs are connected with the risks of developing
glaucoma. Stokes et al., Invest. Ophthalmol. 2000, 41:1629-1638.
Further, a connection between inhibition of 11.beta.-HSD1 and a
lowering of the intraocular pressure was reported. Walker et al.,
poster P3-698 at the Endocrine society meeting Jun. 12-15, 1999,
San Diego. It was shown that administration of the nonspecific
11.beta.-HSD1 inhibitor, carbenoxolone, resulted in the reduction
of the intraocular pressure by 20% in normal patients. In the eye,
11.beta.-HSD1 is expressed exclusively in the basal cells of the
corneal epithelium, the non-pigmented epithelialium of the cornea
(the site of aqueous production), ciliary muscle, and the sphincter
and dilator muscles of the iris. In contrast, the distant isoenzyme
11.beta.-hydroxysteroid dehydrogenase type 2 ("11.beta.-HSD2") is
highly expressed in the non-pigmented ciliary epithelium and
corneal endothelium. No HSDs have been found at the trabecular
meshwork, which is the site of drainage. Therefore, 11.beta.-HSD1
is suggested to have a role in aqueous production.
Glucocorticoids also play an essential role in skeletal development
and function but are detrimental to such development and function
when present in excess. Glucocorticoid-induced bone loss is
partially derived from suppression of osteoblast proliferation and
collagen synthesis, as reported in Kim et al., J. Endocrinol. 1999,
162:371 379. It has been reported that the detrimental effects of
glucocorticoids on bone nodule formation can be lessened by
administration of carbenoxolone, which is a non-specific
11.beta.-HSD1 inhibitor. Bellows et al., Bone 1998, 23:119-125.
Additional reports suggest that 11.beta.-HSD1 may be responsible
for providing increased levels of active glucocorticoid in
osteoclasts, and thus in augmenting bone resorption. Cooper et al.,
Bone 2000, 27:375-381. This data suggests that inhibition of
11-HSD1 may have beneficial effects against osteoporosis via one or
more mechanisms which may act in parallel.
It is known that bile acids inhibit 11.beta.-HSD2 and that such
inhibition results in a shift in the cortisol/cortisone equilibrium
in the favor of cortisol. Quattropani et al., J. Clin. Invest.
November 2001, 108:1299-305. A reduction in the hepatic activity of
11.beta.-HSD2 is therefore predicted to reverse the
cortisol/cortisone equilibrium to favor cortisone, which could
provide therapeutic benefit in diseases such as hypertension.
The various isozymes of the 17-beta-hydroxysteroid dehydrogenases
(17.beta.-HSDs) bind to androgen receptors or estrogen receptors
and catalyze the interconversion of various sex hormones including
estradiol/estrone and testosterone/androstenedione. To date, six
isozymes have been identifed in humans and are expressed in various
human tissues including endometrial tissue, breast tissue, colon
tissue, and in the testes. 17-beta-Hydroxysteroid dehydrogenase
type 2 (17.beta.-HSD2) is expressed in human endometrium and its
activity has been reported to be linked to cervical cancer.
Kitawaki et al., J. Clin. Endocrin. Metab., 2000,
85:1371-3292-3296. 17-beta-Hydroxysteroid dehydrogenase type 3
(17.beta.-HSD3) is expressed in the testes and its modulation may
be useful for the treatment of androgen-related disorders.
Androgens and estrogens are active in their 17.beta.-hydroxy
configurations, whereas their 17-keto derivatives do not bind to
androgen and estrogen receptors and are thus inactive. The
conversion between the active and inactive forms (estradiol/estrone
and testosterone/androstenedione) of sex hormones is catalyzed by
members of the 17.beta.-HSD family. 17.beta.-HSD1 catalyzes the
formation of estradiol in breast tissue, which is important for the
growth of malignant breast tumors. Labrie et al., Mol. Cell.
Endocrinol. 1991, 78: C113-C118. A similar role has been suggested
for 17.beta.-HSD4 in colon cancer. English et al., J. Clin.
Endocrinol. Metab. 1999, 84:2080-2085. 17.beta.-HSD3 is almost
exclusively expressed in the testes and converts androstenedione
into testosterone. Deficiency of this enzyme during fetal
development leads to male pseudohermaphroditism. Geissler et al.,
Nat. Genet. 1994, 7:34-39. Both 17.beta.-HSD3 and various
3.alpha.-HSD isozymes are involved in complex metabolic pathways
which lead to androgen shuffles between inactive and active forms.
Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulation of
certain HSDs can have potentially beneficial effects in the
treatment of androgen- and estrogen-related disorders.
The 20-alpha-hydroxysteroid dehydrogenases (20.alpha.-HSDs)
catalyze the interconversion of progestins (such as between
progesterone and 20.alpha.-hydroxy progesterone). Other substrates
for 20.alpha.-HSDs include 17.alpha.-hydroxypregnenolone or
17.alpha.-hydroxyprogesterone, leading to 20.alpha.-OH steroids.
Several 20.alpha.-HSD isoforms have been identified and
20.alpha.-HSDs are expressed in various tissues, including the
placenta, ovaries, testes and adrenals. Peltoketo, et al., J. Mol.
Endocrinol. 1999, 23:1-11.
The 3-alpha-hydroxysteroid dehydrogenases (3.alpha.-HSDs) catalyze
the interconversion of the androgens dihydrotestosterone (DHT) and
5.alpha.-androstane-3.alpha., 17.beta.-diol and the interconversion
of the androgens DHEA and androstenedione and therefore play an
important role in androgen metabolism. Ge et al., Biology of
Reproduction 1999, 60:855-860.
Despite the previous research done in the field of HSD inhibition,
there remains a need for novel compounds that are potent inhibitors
of the various families of HSDs and efficacious for the treatment
of HSD-mediated conditions such as diabetes, obesity, glaucoma,
osteoporosis, cognitive disorders, immune disorders, depression,
hypertension, and others.
BRIEF SUMMARY OF THE INVENTION
The present invention satisfies this need and others by providing
novel compounds, compositions thereof and methods for modulating
the activity of hydroxysteroid dehydrogenases (HSDs), such as
11.beta.-hydroxysteroid dehydrogenases, 17.beta.-hydroxysteroid
dehydrogenases, 20.alpha.-hydroxysteroid dehydrogenases, and
3.alpha.-hydroxysteroid dehydrogenases, including all isoforms
thereof, including but not limted to 11.beta.-hydroxysteroid
dehydrogenase type 1 (hereinafter "11.beta.-HSD1"),
11.beta.-hydroxysteroid dehydrogenase type 2 (hereinafter
"11.beta.-HSD2"), and 17.beta.-hydroxysteroid dehydrogenase type 3
(hereinafter "17.beta.-HSD3"). In one embodiment, the compounds of
the invention inhibit HSD activity.
The present invention also relates to methods for treating or
preventing diseases or disorders associated with the action of
hydroxysteroid dehydrogenases, comprising administering to a
patient in need thereof a therapeutically effective amount of an
aniline sulfonamide derivative of formula I or a pharmaceutically
acceptable salt, solvate, stereoisomer, or prodrug thereof. The
invention encompasses both selective and non-selective inhibitors
of hydroxysteroid dehydrogenases.
It should be understood that selective and non-selective inhibitors
of hydroxysteroid dehydrogenases each have benefits in the
treatment or prevention of diseases associated with, for example,
abnormal glucose levels or hypothalmic function. The invention also
encompasses selective inhibitors of HSDs. Two types of selectivity
are contemplated, that with respect to selectivity for HSDs as a
class over other types of receptors or gene targets related to
glucose metabolism, or those which are selective for various HSDs
or specific isoforms thereof compared to other HSDs or specific
isoforms thereof.
In one embodiment, the aniline sulfonamide derivatives can act as
selective or non-selective 11.beta.-HSD inhibitors. The compounds
may inhibit the interconversion of inactive 11-keto steroids with
their active hydroxy equivalents. The present invention provides
methods by which the conversion of the inactive to the active form
may be controlled, and useful therapeutic effects which may be
obtained as a result of such control. More specifically, but not
exclusively, the invention is concerned with interconversion
between cortisone and cortisol in humans.
In another embodiment, the aniline sulfonamide derivatives can act
as 11.beta.-HSD inhibitors in vivo.
In another embodiment, the aniline sulfonamide derivatives of the
present invention may be orally active.
The aniline sulfonamide derivatives are also useful for the
modulation of numerous metabolic functions including, but not
limited to, one or more of: (i) regulation of carbohydrate
metabolism, (ii) regulation of protein metabolism, (iii) regulation
of lipid metabolism, (iv) regulation of normal growth and/or
development, (v) influence on cognitive function, (vi) resistance
to stress and mineralocorticoid activity.
The aniline sulfonamide derivatives are additionally useful for
inhibiting hepatic gluconeogenesis, and they also can be effective
to relieve the effects of endogenous glucocorticoids in diabetes
mellitus, obesity (including entripetal obesity), neuronal loss
and/or the cognitive impairment of old age. Thus, in a further
aspect, the invention provides the use of an inhibitor of HSDs in
methods directed to producing one or more therapeutic effects in a
patient to whom the aniline sulfonamide derivative is administered,
said therapeutic effects selected from the group consisting of
inhibition of hepatic gluconeogenesis, an increase in insulin
sensitivity in adipose tissue and muscle, and the prevention of or
reduction in neuronal loss/cognitive impairment due to
glucocorticoid-potentiated neurotoxicity or neural dysfunction or
damage.
The invention further provides methods for treating a condition
selected from the group consisting of: hepatic insulin resistance,
adipose tissue insulin resistance, muscle insulin resistance,
neuronal loss or dysfunction due to glucocorticoid potentiated
neurotoxicity, and any combination of the aforementioned
conditions, the methods comprising administering to a patient in
need thereof a therapeutically effective amount of an aniline
sulfonamide derivative.
The aniline sulfonamide derivatives of the invention are compounds
having Formula I as well as pharmaceutically acceptable salts,
solvates, stereoisomers, or prodrugs thereof.
##STR00002##
In formula I, R.sup.1 is a member selected from the group
consisting of --OH, halogen and (C.sub.1-C.sub.8)haloalkyl. R.sup.2
is selected from the group consisting of (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)hydroxyalkyl and (C.sub.3-C.sub.8)cycloalkyl.
R.sup.3 is selected from the group consisting of halogen,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.8)alkoxy,
(C.sub.2-C.sub.8)hydroxyalkyl and (C.sub.3-C.sub.8)cycloalkyl.
Substituent R.sup.4 is a member selected from the group consisting
of hydrogen, halogen, (C.sub.1-C.sub.8)alkyl and
(C.sub.3-C.sub.8)cycloalkyl.
Substituent R.sup.5 is selected from the group consisting of
hydrogen, --OH, halogen, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)heteroalkyl as defined
below, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)heterocycloalkyl, C(O)R', C(O)NR'.sub.2,
NR'.sub.2, NR'C(O)R', CN, NO.sub.2, aryl, and heteroaryl.
In one embodiment, R.sup.6 may be combined with R.sup.5 to form a
5- to 6-membered fused ring containing L if it is present, the
nitrogen atom to which R.sup.5 is attached, and the sulfur to which
R.sup.6 is attached.
Variable L is selected from the group consisting of a direct bond,
(C.sub.1-C.sub.4)alkylene and (C.sub.2-C.sub.4)alkenylene as
defined below.
In the embodiments described herein, any cycloalkyl portion,
heterocycloalkyl portion, aryl or heteroaryl portion can be
substituted from one to four members selected from the group
consisting of halogen, --CN, --NO.sub.2, (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.8)alkoxy, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.2-C.sub.8)hydroxyalkyl, --C(O)R', --C(O)OR', --NR'C(O)OR'',
--OR', --SR', --OC(O)R', --C(O)N(R').sub.2, --S(O)R'',
--SO.sub.2R'', --SO.sub.2N(R').sub.2, --N(R').sub.2 and
--NR'C(O)R'.
Each occurrence of R' is independently H or an unsubstituted member
selected from the group consisting of (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)heterocycloalkyl,
heteroaryl, aryl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)heterocycloalkyl(C.sub.1-C.sub.6)alkyl,
heteroaryl(C.sub.1-C.sub.6)alkyl, and aryl(C.sub.1-C.sub.6)alkyl.
In some embodiments, two R' groups, when they attached to the same
nitrogen atom, can be combined with the nitrogen atom to which they
are attached to form a heterocycle or heteroaryl group.
Each occurrence of R'' is independently an unsubstituted member
selected from the group consisting of (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl
(C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)hydroxyalkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)heterocycloalkyl,
heteroaryl, aryl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkyl,
heteroaryl(C.sub.1-C.sub.6)alkyl and
aryl(C.sub.1-C.sub.6)alkyl.
One embodiment of the invention provides a pharmaceutical
composition comprising an aniline sulfonamide derivative of Formula
(I) and a pharmaceutically acceptable vehicle, carrier, excipient
or diluent.
In another embodiment, the invention provides methods for treating
insulin-dependent diabetes mellitus comprising administering to a
patient in need thereof a therapeutically effective amount of an
aniline sulfonamide derivative derivative of Formula (I).
In another embodiment, the invention provides methods for treating
non-insulin-dependent diabetes mellitus comprising administering to
a patient in need thereof a therapeutically effective amount of an
aniline sulfonamide derivative of Formula (I).
In yet another embodiment, the invention provides a method for
treating insulin resistance comprising administering to a patient
in need thereof a therapeutically effective amount of an aniline
sulfonamide derivative of Formula (I).
In still another embodiment, the invention provides a method for
treating obesity comprising administering to a patient in need
thereof a therapeutically effective amount of an aniline
sulfonamide derivative of Formula (I).
In another embodiment, the invention provides a method for
modulating cortisol production comprising administering to a
patient in need thereof a therapeutically effective, amount of an
aniline sulfonamide derivative of Formula (I).
In another embodiment, the invention provides methods for
modulating hepatic glucose production comprising administering to a
patient in need thereof a therapeutically effective amount of an
aniline sulfonamide derivative of Formula (I).
In another embodiment, the invention provides a method for
modulating hypothalamic function comprising administering to a
patient in need thereof a therapeutically effective amount of an
aniline sulfonamide derivative of Formula (I).
In one embodiment, the invention provides a method for treating a
hydroxysteroid dehydrogenase-mediated condition or disorder
comprising administering to a patient in need thereof a
therapeutically effective amount of an aniline sulfonamide
derivative of Formula (I).
In another embodiment, the invention provides a method for
modulating the function of a hydroxysteroid dehydrogenase in a cell
comprising administering to a patient in need thereof a
therapeutically effective amount of an aniline sulfonamide
derivative of Formula (I).
In a further embodiment, the invention provides a method for
modulating a hydroxysteroid dehydrogenase, comprising administering
to a patient in need thereof a therapeutically effective amount of
an aniline sulfonamide derivative of Formula (I).
In still another embodiment, the invention provides a method for
treating an 11.beta.-HSD1-mediated condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
In yet another embodiment, the invention provides a method for
modulating the function of 11.beta.-HSD1 in a cell comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
In a further embodiment, the invention provides a method for
modulating 11.beta.-HSD1, comprising administering to a patient in
need thereof a therapeutically effective amount of an aniline
sulfonamide derivative of Formula (I).
In one embodiment, the invention provides a method for treating an
11.beta.-HSD2-mediated condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
In another embodiment, the invention provides a method for
modulating the function of 11.beta.-HSD2 in a cell comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
In a further embodiment, the invention provides a method for
modulating 11.beta.-HSD2, comprising administering to a patient in
need thereof a therapeutically effective amount of an aniline
sulfonamide derivative of Formula (I).
In one embodiment, the invention provides a method for treating an
17.beta.-HSD3-mediated condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
In another embodiment, the invention provide a method for
modulating the function of 17.beta.-HSD3 in a cell comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
In a further embodiment, the invention provides a method for
modulating 17.beta.-HSD3, comprising administering to a patient in
need thereof a therapeutically effective amount of an aniline
sulfonamide derivative of Formula (I).
These and other embodiments of this invention will be evident upon
reference to the following detailed description. To that end,
certain patent and other documents are cited herein to more
specifically set forth various embodiments of this invention. Each
of these documents are hereby incorporated by reference in their
entireties.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the terms have the following meanings:
The term "alkyl" as used herein refers to a straight or branched
chain, saturated hydrocarbon having the indicated number of carbon
atoms. For example, (C.sub.1-C.sub.6)alkyl is meant to include, but
is not limited to methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,
isohexyl, and neohexyl. An alkyl group can be unsubstituted or
optionally substituted with one or more substituents as described
herein below.
The term "alkenyl" as used herein refers to a straight or branched
chain unsaturated hydrocarbon having the indicated number of carbon
atoms and at least one double bond. Examples of a
(C.sub.2-C.sub.8)alkenyl group include, but are not limited to,
ethylene, propylene, 1-butylene, 2-butylene, isobutylene,
sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene,
3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, isoheptene,
1-octene, 2-octene, 3-octene, 4-octene, and isooctene. An alkenyl
group can be unsubstituted or optionally substituted with one or
more substituents as described herein below.
The term "alkynyl" as used herein refers to a straight or branched
chain unsaturated hydrocarbon having the indicated number of carbon
atoms and at least one triple bond. Examples of a
(C.sub.2-C.sub.8)alkynyl group include, but are not limited to,
acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne,
1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne,
1-octyne, 2-octyne, 3-octyne and 4-octyne. An alkynyl group can be
unsubstituted or optionally substituted with one or more
substituents as described herein below.
The term "alkylene" refers to a divalent alkyl group (e.g., an
alkyl group attached to two other moieties, typically as a linking
group). Examples of a (C.sub.1-C.sub.7)alkylene include
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, as
well as branched versions thereof. An alkylene group can be
unsubstituted or optionally substituted with one or more
substituents as described herein below.
The term "alkenylene" refers to a divalent alkene group (e.g., an
alkene group attached to two other moieties, typically as a linking
group). Examples of a (C.sub.2-C.sub.7)alkenylene include
--CH.dbd.CH--, --CH.dbd.CHCH.sub.2--,
--CH.dbd.CHCH.sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2--,
--CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.dbd.CHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, as well as
branched versions and structure isomers thereof. An alkenylene
group can be unsubstituted or optionally substituted with one or
more substituents as described herein below.
The term "alkoxy" as used herein refers to an --O-alkyl group
having the indicated number of carbon atoms. For example, a
(C.sub.1-C.sub.6)alkoxy group includes --O-methyl, --O-ethyl,
--O-propyl, --O-isopropyl, --O-butyl, --O-sec-butyl,
--O-tert-butyl, --O-pentyl, --O-isopentyl, --O-neopentyl,
--O-hexyl, --O-isohexyl, and --O-neohexyl.
The term "aminoalkyl," as used herein, refers to an alkyl group
(typically one to six carbon atoms) wherein from one or more of the
C.sub.1-C.sub.6 alkyl group's hydrogen atoms is replaced with an
amine of formula --N(R.sup.a).sub.2, wherein each occurrence of
R.sup.a is independently --H or (C.sub.1-C.sub.6)alkyl. Examples of
aminoalkyl groups include, but are not limited to,
--CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2N(CH.sub.3).sub.2, t-butylaminomethyl,
isopropylaminomethyl and the like.
The term "aryl" as used herein refers to a 6- to 14-membered
monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system.
Examples of an aryl group include phenyl and naphthyl. An aryl
group can be unsubstituted or optionally substituted with one or
more substituents as described herein below.
The term "cycloalkyl" as used herein refers to a 3- to 14-membered
saturated or unsaturated non-aromatic monocyclic, bicyclic or
tricyclic hydrocarbon ring system. Included in this class are
cycloalkyl groups which are fused to a benzene ring. Representative
cycloalkyl groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl,
cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl,
1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctyl,
cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl,
-1,3,5-cyclooctatrienyl, decahydronaphthalene,
octahydronaphthalene, hexahydronaphthalene, octahydroindene,
hexahydroindene, tetrahydroinden, decahydrobenzocycloheptene,
octahydrobenzocycloheptene, hexahydrobenzocycloheptene,
tetrahydrobenzocyclopheptene, dodecahydroheptalene,
decahydroheptalene, octahydroheptalene, hexahydroheptalene, and
tetrahydroheptalene. A cycloalkyl group can be unsubstituted or
optionally substituted with one or more substituents as described
herein below.
The term "halo" as used herein refers to --F, --Cl, --Br or
--I.
The term "haloalkyl," as used herein, refers to a C.sub.1-C.sub.6
alkyl group wherein from one or more of the C.sub.1-C.sub.6 alkyl
group's hydrogen atom is replaced with a halogen atom, which can be
the same or different. Examples of haloalkyl groups include, but
are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl,
4-chlorobutyl, 3-bromopropyl, pentachloroethyl, and
1,1,1-trifluoro-2-bromo-2-chloroethyl.
The term "heteroalkyl," by itself or in combination with another
term, means, unless otherwise stated, a stable straight or branched
chain, or cyclic hydrocarbon radical, or combinations thereof,
consisting of carbon atoms and from one to three heteroatoms
selected from the group consisting of O, N and S, and wherein the
nitrogen and sulfur atoms may optionally be oxidized and the
nitrogen heteroatom may optionally be quaternized. The
heteroatom(s) O, N and S may be placed at any position of the
heteroalkyl group. Examples include
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2--S(O)--CH.sub.3,
--CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3, and
--CH.sub.2--CH.dbd.N--OCH.sub.3. Up to two heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3. When
a prefix such as (C.sub.2-C.sub.8) is used to refer to a
heteroalkyl group, the number of carbons (2 to 8, in this example)
is meant to include the heteroatoms as well. For example, a
C.sub.2-heteroalkyl group is meant to include, for example,
--CH.sub.2OH (one carbon atom and one heteroatom replacing a carbon
atom) and --CH.sub.2SH.
To further illustrate the definition of a heteroalkyl group, where
the heteroatom is oxygen, a heteroalkyl group is an oxyalkyl group.
For instance, (C.sub.2-C.sub.5)oxyalkyl is meant to include, for
example --CH.sub.2--O--CH.sub.3 (a C.sub.3-oxyalkyl group with two
carbon atoms and one oxygen replacing a carbon atom),
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, and the like.
The term "heteroalkylene" by itself or as part of another
substituent means a divalent radical derived from heteroalkyl, as
exemplified by --CH.sub.2--CH.sub.2--S--CH.sub.2CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied
The term "heteroaryl" as used herein refers to an aromatic
heterocycle ring of 5 to 14 members and having at least one
heteroatom selected from nitrogen, oxygen and sulfur, and
containing at least 1 carbon atom, including monocyclic, bicyclic,
and tricyclic ring systems. Representative heteroaryls are
triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl,
thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl,
oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,
benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl,
quinazolinyl, pyrimidyl, azepinyl, oxepinyl, quinoxalinyl and
oxazolyl. A heteroaryl group can be unsubstituted or optionally
substituted with one or more substituents as described herein
below.
As used herein, the term "heteroatom" is meant to include oxygen
(O), nitrogen (N), and sulfur (S).
As used herein, the term "heterocycle" refers to 3- to 14-membered
ring systems which are either saturated, unsaturated, or aromatic,
and which contains from 1 to 4 heteroatoms independently selected
from nitrogen, oxygen and sulfur, and wherein the nitrogen and
sulfur heteroatoms may be optionally oxidized, and the nitrogen
heteroatom may be optionally quaternized, including, including
monocyclic, bicyclic, and tricyclic ring systems. The bicyclic and
tricyclic ring systems may encompass a heterocycle or heteroaryl
fused to a benzene ring. The heterocycle may be attached via any
heteroatom or carbon atom. Heterocycles include heteroaryls as
defined above. Representative examples of heterocycles include, but
are not limited to, aziridinyl, oxiranyl, thiiranyl, triazolyl,
tetrazolyl, azirinyl, diaziridinyl, diazirinyl, oxaziridinyl,
azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl,
piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, diazinyl,
dioxanyl, triazinyl, tetrazinyl, imidazolyl, tetrazolyl,
pyrrolidinyl, isoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl,
benzoxazolyl, benzisoxazolyl, thiazolyl, benzthiazolyl, thiophenyl,
pyrazolyl, triazolyl, pyrimidinyl, benzimidazolyl, isoindolyl,
indazolyl, benzodiazolyl, benzotriazolyl, benzoxazolyl,
benzisoxazolyl, purinyl, indolyl, isoquinolinyl, quinolinyl and
quinazolinyl. A heterocycle group can be unsubstituted or
optionally substituted with one or more substituents as described
herein below.
The term "heterocycloalkyl," by itself or in combination with other
terms, represents, unless otherwise stated, cyclic versions of
"heteroalkyl". Thus, the term "heterocycloalkyl" is meant to be
included in the term "heteroalkyl". Additionally, a heteroatom can
occupy the position at which the heterocycle is attached to the
remainder of the molecule. Examples of heterocycloalkyl include
1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,
1-piperazinyl, 2-piperazinyl, and the like.
The term "hydroxyalkyl," as used herein, refers to an alkyl group
having the indicated number of carbon atoms wherein one or more of
the alkyl group's hydrogen atoms is replaced with an --OH group.
Examples of hydroxyalkyl groups include, but are not limited to,
--CH.sub.2OH, --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, and branched
versions thereof.
Substituents for the alkyl radicals (as well as those groups
referred to as alkylene, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a
variety of groups selected from: --OR', .dbd.O, .dbd.NR',
.dbd.N--OR', --NR'R'', --SR', -halo, --SiR'R''R''', --OC(O)R',
--C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
--NR'''C(O)NR'R'', --NR'''SO.sub.2NR'R'', --NR''CO.sub.2R',
--NHC(NH.sub.2).dbd.NH, --NR'C(NH.sub.2).dbd.NH,
--NHC(NH.sub.2).dbd.NR', --S(O)R', --SO.sub.2R', --SO.sub.2NR'R'',
--NR''SO.sub.2R', --CN and --NO.sub.2, in a number ranging from
zero to three, with those groups having zero, one or two
substituents being exemplary. R', R'' and R''' each independently
refer to hydrogen, unsubstituted (C.sub.1-C.sub.8)alkyl,
unsubstituted hetero(C.sub.1-C.sub.8)alkyl, unsubstituted aryl and
aryl substituted with one to three substituents selected from
-halo, unsubstituted alkyl, unsubstituted alkoxy, unsubstituted
thioalkoxy and unsubstituted aryl(C.sub.1-C.sub.4)alkyl. When R'
and R'' are attached to the same nitrogen atom, they can be
combined with the nitrogen atom to form a 5-, 6- or 7-membered
ring. For example, --NR'R'' is meant to include 1-pyrrolidinyl and
4-morpholinyl. Typically, an alkyl or heteroalkyl group will have
from zero to three substituents, with those groups having two or
fewer substituents being exemplary of the present invention. An
alkyl or heteroalkyl radical can be unsubstituted or
monosubstituted. In some embodiments, an alkyl or heteroalkyl
radical will be unsubstituted. From the above discussion of
substituents, one of skill in the art will understand that the term
"alkyl" is meant to include groups such as trihaloalkyl (e.g.,
--CF.sub.3 and --CH.sub.2CF.sub.3).
Exemplary substituents for the alkyl and heteroalkyl radicals
include but are not limited to --OR', .dbd.O, --NR'R'', --SR',
-halo, --SiR'R''R''', --OC(O)R', -C(O)R', --CO.sub.2R',
--C(O)NR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR''CO.sub.2R',
--NR'''SO.sub.2NR'R'', --S(O)R', --SO.sub.2R', --SO.sub.2NR'R'',
--NR''SO.sub.2R', --CN and --NO.sub.2, where R', R'' and R''' are
as defined above. Typical substituents can be selected from: --OR',
.dbd.O, --NR'R'', -halo, --OC(O)R', --CO.sub.2R', --C(O)NR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR''CO.sub.2R',
--NR'''SO.sub.2NR'R'', --SO.sub.2R', --SO.sub.2NR'R'',
--NR''SO.sub.2R'--CN and --NO.sub.2.
Similarly, substituents for the aryl and heteroaryl groups are
varied and selected from: -halo, --OR', --OC(O)R', --NR'R'', --SR',
--R', --CN, --NO.sub.2, --CO.sub.2R', --C(O)NR'R'', --C(O)R',
--OC(O)NR'R'', --NR''C(O)R', --NR''CO.sub.2R', --NR'''C(O)NR'R'',
--NR'''SO.sub.2NR'R'', --NHC(NH.sub.2).dbd.NH,
--NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R',
--SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R', --N.sub.3,
--CH(Ph).sub.2, perfluoroalkoxy and
perfluoro(C.sub.1-C.sub.4)alkyl, in a number ranging from zero to
the total number of open valences on the aromatic ring system; and
where R', R'' and R''' are independently selected from hydrogen,
unsubstituted (C.sub.1-C.sub.8)alkyl, unsubstituted
hetero(C.sub.1-C.sub.8)alkyl, unsubstituted aryl, unsubstituted
heteroaryl, unsubstituted aryl(C.sub.1-C.sub.4)alkyl and
unsubstituted aryloxy(C.sub.1-C.sub.4)alkyl. Typically, an aryl or
heteroaryl group will have from zero to three substituents, with
those groups having two or fewer substituents being exemplary in
the present invention. In one embodiment of the invention, an aryl
or heteroaryl group will be unsubstituted or monosubstituted. In
another embodiment, an aryl or heteroaryl group will be
unsubstituted.
Two of the substituents on adjacent atoms of the aryl or heteroaryl
ring in an aryl or heteroaryl group may optionally be replaced with
a substituent of the formula -T-C(O)--(CH.sub.2).sub.q-U-, wherein
T and U are independently --NH--, --O--, --CH.sub.2-- or a single
bond, and q is an integer of from 0 to 2. Alternatively, two of the
substituents on adjacent atoms of the aryl or heteroaryl ring may
optionally be replaced with a substituent of the formula
-A-(CH.sub.2).sub.r-B-, wherein A and B are independently
--CH.sub.2--, --O--, --NH--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2NR'-- or a single bond, and r is an integer of from 1
to 3. One of the single bonds of the new ring so formed may
optionally be replaced with a double bond. Alternatively, two of
the substituents on adjacent atoms of the aryl or heteroaryl ring
may optionally be replaced with a substituent of the formula
--(CH.sub.2).sub.s-X--(CH.sub.2).sub.t--, where s and t are
independently integers of from 0 to 3, and X is --O--, --NR'--,
--S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituent R' in --NR'-- and --S(O).sub.2NR'-- is selected from
hydrogen or unsubstituted (C.sub.1-C.sub.6)alkyl.
It is to be understood that the substituent --CO.sub.2H, as used
herein, may be optionally replaced with bioisosteric replacements
such as:
##STR00003## and the like. See, e.g., The Practice of Medicinal
Chemistry; Wermuth, C. G., Ed.; Academic Press: New York, 1996; p.
203.
The aniline sulfonamide derivative of formula I can also exist in
various isomeric forms, including configurational, geometric and
conformational isomers, as well as existing in various tautomeric
forms, particularly those that differ in the point of attachment of
a hydrogen atom. As used herein, the term "isomer" is intended to
encompass all isomeric forms of an aniline sulfonamide derivative,
including tautomeric forms of the compound.
Certain aniline sulfonamide derivatives may have asymmetric centers
and therefore exist in different enantiomeric and diastereomeric
forms. An aniline sulfonamide derivative can be in the form of an
optical isomer or a diastereomer. Accordingly, the invention
encompasses aniline sulfonamide derivatives and their uses as
described herein in the form of their optical isomers,
diasteriomers and mixtures thereof, including racemic mixtures.
Optical isomers of the aniline sulfonamide derivatives can be
obtained by known techniques such as asymmetric synthesis, chiral
chromatography, simulated moving bed technology or via chemical
separation of stereoisomers through the employment of optically
active resolving agents.
As used herein and unless otherwise indicated, the term
"stereoisomer" means one stereoisomer of a compound that is
substantially free of other stereoisomers of that compound. For
example, a stereomerically pure compound having one chiral center
will be substantially free of the opposite enantiomer of the
compound. A stereomerically pure compound having two chiral centers
will be substantially free of other diastereomers of the compound.
A typical stereomerically pure compound comprises greater than
about 80% by weight of one stereoisomer of the compound and less
than about 20% by weight of other stereoisomers of the compound,
for example greater than about 90% by weight of one stereoisomer of
the compound and less than about 10% by weight of the other
stereoisomers of the compound, or greater than about 95% by weight
of one stereoisomer of the compound and less than about 5% by
weight of the other stereoisomers of the compound, or greater than
about 97% by weight of one stereoisomer of the compound and less
than about 3% by weight of the other stereoisomers of the
compound.
It should be noted that if there is a discrepancy between a
depicted structure and a name given to that structure, the depicted
structure controls. In addition, if the stereochemistry of a
structure or a portion of a structure is not indicated with, for
example, bold, wedged, or dashed lines, the structure or portion of
the structure is to be interpreted as encompassing all
stereoisomers of it.
An aniline sulfonamide derivative can be in the form of a
pharmaceutically acceptable salt. Depending on the structure of the
derivative, the phrase "pharmaceutically acceptable salt," as used
herein, refers to a pharmaceutically acceptable organic or
inorganic acid or base salt of an aniline sulfonamide derivative.
Representative pharmaceutically acceptable salts include, e.g.,
alkali metal salts, alkali earth salts, ammonium salts,
water-soluble and water-insoluble salts, such as the acetate,
amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,
benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,
butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,
citrate, clavulariate, dihydrochloride, edetate, edisylate,
estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts. Furthermore,
a pharmaceutically acceptable salt can have more than one charged
atom in its structure. In this instance the pharmaceutically
acceptable salt can have multiple counterions. Hence, a
pharmaceutically acceptable salt can have one or more charged atoms
and/or one or more counterions.
As used herein, the term "isolated and purified form" means that
when isolated (e.g., from other components of a synthetic organic
chemical reaction mixture), the isolate contains at least 30%, at
least 35%, at least 40%, at least 45%, at least 50%, at least 55%,
at least 60%, at least 65%, at least 70%, at least 75%, at least
80%, at least 85%, at least 90%, at least 95% or at least 98% of an
aniline sulfonamide derivative by weight of the isolate. In one
embodiment, the isolate contains at least 95% of an aniline
sulfonamide derivative by weight of the isolate.
As used herein, the term "prodrug" means a derivative of a compound
that can hydrolyze, oxidize, or otherwise react under biological
conditions (in vitro or in vivo) to provide an active compound,
particularly an aniline sulfonamide derivative. Examples of
prodrugs include, but are not limited to, derivatives and
metabolites of an aniline sulfonamide derivative that include
biohydrolyzable groups such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues (e.g., monophosphate, diphosphate or triphosphate). In
some embodiments, prodrugs of compounds with carboxyl functional
groups are the lower alkyl esters of the carboxylic acid. The
carboxylate esters are conveniently formed by esterifying any of
the carboxylic acid moieties present on the molecule. Prodrugs can
typically be prepared using well-known methods, such as those
described by Burger's Medicinal Chemistry and Drug Discovery
6.sup.th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and
Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic
Publishers Gmfh).
As used herein, the terms "treat", "treating" and "treatment" refer
to the eradication or amelioration of a disease or symptoms
associated with a disease. In certain embodiments, such terms refer
to minimizing the spread or worsening of the disease resulting from
the administration of one or more prophylactic or therapeutic
agents to a patient with such a disease.
As used herein, the terms "prevent", "preventing" and "prevention"
refer to the prevention of the onset, recurrence or spread of the
disease in a patient resulting from the administration of a
prophylactic or therapeutic agent.
The term "effective amount" as used herein refers to an amount of
an aniline sulfonamide derivative or other active ingredient
sufficient to provide a therapeutic or prophylactic benefit in the
treatment or prevention of a disease or to delay or minimize
symptoms associated with a disease. Further, a therapeutically
effective amount with respect to an aniline sulfonamide derivative
means that amount of therapeutic agent alone, or in combination
with other therapies, that provides a therapeutic benefit in the
treatment or prevention of a disease. Used in connection with an
aniline sulfonamide derivative, the term can encompass an amount
that improves overall therapy, reduces or avoids symptoms or causes
of disease, or enhances the therapeutic efficacy of or synergies
with another therapeutic agent.
As used herein, "syndrome X" refers to a collection of
abnormalities including hyperinsulinemia, obesity, elevated levels
of triglycerides, uric acid, fibrinogen, small dense LDL particles
and plasminogen activator inhibitor 1 (PAI-1), and decreased levels
of HDL cholesterol. Syndrome X is further meant to include
metabolic syndrome.
The terms "modulate", "modulation" and the like refer to the
ability of a compound to increase or decrease the function, or
activity of, for example, 11.beta.-HSD1. "Modulation", as used
herein in its various forms, is intended to encompass inhibition,
antagonism, partial antagonism, activation, agonism and/or partial
agonism of the activity associated with 11.beta.-HSD1.
11.beta.-HSD1 inhibitors are compounds that, e.g., bind to,
partially or totally block stimulation, decrease, prevent, delay
activation, inactivate, desensitize, or down regulate signal
transduction. 11.beta.-HSD1 activators are compounds that, e.g.,
bind to, stimulate, increase, open, activate, facilitate, enhance
activation, sensitize or up regulate signal transduction. The
ability of a compound to modulate 11.beta.-HSD1 can be demonstrated
in an enzymatic assay or a cell-based assay. For example, the
inhibition of 11.beta.-HSD1 may decrease cortisol levels in a
patient and/or increase cortisone levels in a patient by blocking
the conversion of cortisone to cortisol. Alternatively, the
inhibition of 11.beta.-HSD2 can increase cortisol levels in a
patient and/or decrease cortisone levels in a patient by blocking
the conversion of cortisol to cortisone.
A "patient" includes an animal (e.g., cow, horse, sheep, pig,
chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea
pig), in one embodiment a mammal such as a non-primate or a primate
(e.g., monkey and human), and in another embodiment a human. In a
one embodiment, a patient is a human. In other embodiments, the
patient is a human infant, child, adolescent or adult.
The term "HSD" as used herein, refers to hydroxysteroid
dehydrogenase enzymes in general, including, but not limited to,
11-beta-hydroxysteroid dehydrogenases (11.beta.-HSDs),
17-beta-hydroxysteroid dehydrogenases (17.beta.-HSDs),
20-alpha-hydroxysteroid dehydrogenases (20.alpha.-HSDs),
3-alpha-hydroxysteroid dehydrogenases (3.alpha.-HSDs), and all
isoforms thereof.
The term "11.beta.-HSD1" as used herein, refers to the
11-beta-hydroxysteroid dehydrogenase type 1 enzyme, variant, or
isoform thereof. 11.beta.-HSD1 variants include proteins
substantially homologous to native 11.beta.-HSD1, i.e., proteins
having one or more naturally or non-naturally occurring amino acid
deletions, insertions or substitutions (e.g., 11.beta.-HSD1
derivatives, homologs and fragments). The amino acid sequence of a
11.beta.-HSD1 variant can be at least about 80% identical to a
native 11.beta.-HSD1, or at least about 90% identical, or at least
about 95% identical.
The term "11.beta.-HSD2" as used herein, refers to the
11-beta-hydroxysteroid dehydrogenase type 2 enzyme, variant, or
isoform thereof. 11.beta.-HSD2 variants include proteins
substantially homologous to native 11.beta.-HSD2, i.e., proteins
having one or more naturally or non-naturally occurring amino acid
deletions, insertions or substitutions (e.g., 11.beta.-HSD2
derivatives, homologs and fragments). The amino acid sequence of a
11.beta.-HSD2 variant can be at least about 80% identical to a
native 11.beta.-HSD2, or at least about 90% identical, or at least
about 95% identical. (see Bart et al., J. Med. Chem., 2002,
45:3813-3815).
The term "17.beta.-HSD3" as used herein, refers to the
17-beta-hydroxysteroid dehydrogenase type 3 enzyme, variant, or
isoform thereof. 17.beta.-HSD3 variants include proteins
substantially homologous to native 17.beta.-HSD3, i.e., proteins
having one or more naturally or non-naturally occurring amino acid
deletions, insertions or substitutions (e.g., 17.beta.-HSD3
derivatives, homologs and fragments). The amino acid sequence of a
17.beta.-HSD3 variant can be at least about 80% identical to a
native 17.beta.-HSD3, or at least about 90% identical, or at least
about 95% identical.
As used herein, the term "HSD-responsive condition or disorder" and
related terms and phrases refer to a condition or disorder that
responds favorably to modulation of a hydroxysteroid dehydrogenase
enzyme (HSD). Favorable responses to HSD modulation include
alleviation or abrogation of the disease and/or its attendant
symptoms, inhibition of the disease, i.e., arrest or reduction of
the development of the disease, or its clinical symptoms, and
regression of the disease or its clinical symptoms. An
HSD-responsive condition or disease may be completely or partially
responsive to HSD modulation. An HSD-responsive condition or
disorder may be associated with inappropriate, e.g., less than or
greater than normal, HSD activity and at least partially responsive
to or affected by HSD modulation (e.g., an HSD inhibitor results in
some improvement in patient well-being in at least some patients).
Inappropriate HSD functional activity might arise as the result of
HSD expression in cells which normally do not express HSD,
decreased HSD expression or increased HSD expression. An
HSD-responsive condition or disorder may include condition or
disorder mediated by any HSD or isoform thereof.
As used herein, the term "11.beta.-HSD1-responsive condition or
disorder" and related terms and phrases refer to a condition or
disorder that responds favorably to modulation of 11.beta.-HSD1
activity. Favorable responses to 11.beta.-HSD1 modulation include
alleviation or abrogation of the disease and/or its attendant
symptoms, inhibition of the disease, i.e., arrest or reduction of
the development of the disease, or its clinical symptoms, and
regression of the disease or its clinical symptoms. An
11.beta.-HSD1-responsive condition or disease may be completely or
partially responsive to 11.beta.-HSD1 modulation. An
11.beta.-HSD1-responsive condition or disorder may be associated
with inappropriate, e.g., less than or greater than normal,
11.beta.-HSD1 activity and at least partially responsive to or
affected by 11.beta.-HSD1 modulation (e.g., a 11.beta.-HSD1
inhibitor results in some improvement in patient well-being in at
least some patients). Inappropriate 11.beta.-HSD1 functional
activity might arise as the result of 11.beta.-HSD1 expression in
cells which normally do not express 11.beta.-HSD1, decreased
11.beta.-HSD1 expression or increased 11.beta.-HSD1 expression. A
11.beta.-HSD1-responsive condition or disorder may include a
11.beta.-HSD1-mediated condition or disorder.
As used herein, the term "11.beta.-HSD2-responsive condition or
disorder" and related terms and phrases refer to a condition or
disorder that responds favorably to modulation of 11.beta.-HSD2
activity. Favorable responses to 11.beta.-HSD2 modulation include
alleviation or abrogation of the disease and/or its attendant
symptoms, inhibition of the disease, i.e., arrest or reduction of
the development of the disease, or its clinical symptoms, and
regression of the disease or its clinical symptoms. An
11.beta.-HSD2-responsive condition or disease may be completely or
partially responsive to 11.beta.-HSD2 modulation. An
11.beta.-HSD2-responsive condition or disorder may be associated
with inappropriate, e.g., less than or greater than normal,
11.beta.-HSD2 activity and at least partially responsive to or
affected by 11.beta.-HSD2 modulation (e.g., a 11.beta.-HSD2
inhibitor results in some improvement in patient well-being in at
least some patients).
As used herein, the term "17.beta.-HSD3-responsive condition or
disorder" and related terms and phrases refer to a condition or
disorder that responds favorably to modulation of 17.beta.-HSD3
activity. Favorable responses to 17.beta.-HSD3 modulation include
alleviation or abrogation of the disease and/or its attendant
symptoms, inhibition of the disease, i.e., arrest or reduction of
the development of the disease, or its clinical symptoms, and
regression of the disease or its clinical symptoms. An
17.beta.-HSD3-responsive condition or disease may be completely or
partially responsive to 17.beta.-HSD3 modulation. An
17.beta.-HSD3-responsive condition or disorder may be associated
with inappropriate, e.g., less than or greater than normal,
17.beta.-HSD3 activity and at least partially responsive to or
affected by 17.beta.-HSD3 modulation (e.g., a 17.beta.-HSD3
inhibitor results in some improvement in patient well-being in at
least some patients). Inappropriate 17.beta.-HSD3 functional
activity might arise as the result of 17.beta.-HSD3 expression in
cells which normally do not express 17.beta.-HSD3, decreased
17.beta.-HSD3 expression or increased 17.beta.-HSD3 expression. A
17.beta.-HSD3-responsive condition or disorder may include a
17.beta.-HSD3-mediated condition or disorder.
As used herein, the term "HSD-mediated condition or disorder" and
related terms and phrases refer to a condition or disorder
characterized by inappropriate, e.g., less than or greater than
normal, activity of a hydroxysteroid dehydrogenase (HSD). An
HSD-mediated condition or disorder may be completely or partially
characterized by inappropriate HSD activity. However, an
HSD-mediated condition or disorder is one in which modulation of an
HSD results in some effect on the underlying condition or disease
(e.g., an HSD inhibitor results in some improvement in patient
well-being in at least some patients).
As used herein, the term "11.beta.-HSD1-mediated condition or
disorder" and related terms and phrases refer to a condition or
disorder characterized by inappropriate, e.g., less than or greater
than normal, 11.beta.-HSD1 activity. A 11.beta.-HSD1-mediated
condition or disorder may be completely or partially characterized
by inappropriate 11.beta.-HSD1 activity. However, a
11.beta.-HSD1-mediated condition or disorder is one in which
modulation of 11.beta.-HSD1 results in some effect on the
underlying condition or disease (e.g., a 11.beta.-HSD1 inhibitor
results in some improvement in patient well-being in at least some
patients).
As used herein, the tern "11.beta.-HSD2-mediated condition or
disorder" and related terms and phrases refer to a condition or
disorder characterized by inappropriate, e.g., less than or greater
than normal, 11.beta.-HSD2 activity. A 11.beta.-HSD2-mediated
condition or disorder may be completely or partially characterized
by inappropriate 11.beta.-HSD2 activity. However, a
11.beta.-HSD2-mediated condition or disorder is one in which
modulation of 11.beta.-HSD2 results in some effect on the
underlying condition or disease (e.g., a 11.beta.-HSD2 inhibitor
results in some improvement in patient well-being in at least some
patients).
As used herein, the term "17.beta.-HSD3-mediated condition or
disorder" and related terms and phrases refer to a condition or
disorder characterized by inappropriate, e.g., less than or greater
than normal, 17.beta.-HSD3 activity. A 17.beta.-HSD3-mediated
condition or disorder may be completely or partially characterized
by inappropriate 17.beta.-HSD3 activity. However, a
17.beta.-HSD3-mediated condition or disorder is one in which
modulation of 17.beta.-HSD3 results in some effect on the
underlying condition or disease (e.g., a 17.beta.-HSD3 inhibitor
results in some improvement in patient well-being in at least some
patients).
The following abbreviations are used herein and have the indicated
definitions: DMEM is Dulbecco's Modified Eagle Medium; Et.sub.3N is
triethylamine; EtOAc is ethyl acetate; MeOH is methanol; MS is mass
spectrometry; NMR is nuclear magnetic resonance; PBS is
phosphate-buffered saline; SPA is scintillation proximity assay;
THF is tetrahydrofuran; and TMS is trimethylsilyl.
Compounds of the Invention
The present invention provides compounds of Formula (I) as well as
their pharmaceutically acceptable salts, solvates, stereoisomers,
or prodrugs thereof, collectively referred to as the "The aniline
sulfonamide derivatives."
##STR00004##
Variables R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and
L are defined as set forth above in the summary of the
invention.
In combination with any of the embodiments described herein, one
embodiment provides for L being a direct bond.
In other embodiments, R.sup.5 is (C.sub.1-C.sub.8)alkyl. For
example, R.sup.5 can be a (C.sub.1-C.sub.3)alkyl. Specific examples
of R.sup.5 include but are not limited to methyl, ethyl, and
isopropyl. In one embodiment, R.sup.5 is isopropyl.
In yet other embodiments, R.sup.5 is (C.sub.3-C.sub.8)cycloalkyl.
Specific (C.sub.3-C.sub.8)cycloalkyl groups include but are not
limited to cyclopropyl and cyclobutyl.
Other embodiments provide for R.sup.6 being aryl. In some
embodiments, R.sup.6 is aryl optionally substituted with one to
four substiuents. Thus, for example, R.sup.6 can be
dichloro-substituted phenyl, 2-chloro-5-cyano-phenyl,
2-chloro-phenyl, or 2-chloro-5-trifluoromethyl-phenyl.
In further embodiments, R.sup.5 is selected from
(C.sub.1-C.sub.8)alkyl and halo-(C.sub.1-C.sub.8)alkyl, and R.sup.6
is selected from phenyl and substituted phenyl. For example,
R.sup.5 can be selected from methyl, ethyl and isopropyl and
R.sup.6 can be halosubstitued phenyl or CN-substituted phenyl.
In other embodiments, R.sup.5 is a C.sub.3-C.sub.8 cycloalkyl
moiety and R.sup.6 is selected from phenyl and substituted phenyl.
In these embodiments, R.sup.5 can be cyclopropyl or cyclobutyl.
In some embodiments, optionally in combination with any other
embodiment described herein, R.sup.1 is --OH.
In still other embodiments, R.sup.2 is (C.sub.1-C.sub.8)haloalkyl
and and R.sup.3 is (C.sub.1-C.sub.8)alkyl. For example, the
(C.sub.1-C.sub.8)haloalkyl group can be trifluoromethyl.
Illustrative of a (C.sub.1-C.sub.8)alkyl group is methyl.
Further embodiments provide for compounds wherein R.sup.1 is --OH,
and wherein R.sup.2 is trifluoromethyl and R.sup.3 is methyl.
Specific examples satisfying these structural requirements are
wherein R.sup.1, R.sup.2, and R.sup.3, together with the carbon
atom to which they are attached, are an (S)-trifluoromethyl
carbinol group of the formula:
##STR00005##
Alternatively, R.sup.1, R.sup.2, and R.sup.3, together with the
carbon atom to which they are attached, are an (R)-trifluoromethyl
carbinol group of the formula:
##STR00006##
The aniline sulfonamide derivatives can have asymmetric centers and
therefore exist in different enantiomeric and diastereomeric forms.
This invention relates to the use of all optical isomers and
stereoisomers of the aniline sulfonamide derivatives, and mixtures
thereof, and to all pharmaceutical compositions and methods of
treatment that may employ or contain them.
It should be noted that racemates, racemic mixtures, and
stereoisomers, particularly diastereomeric mixtures or
diastereomerically pure compounds and enantiomers or
enantiomerically pure compounds of the above are all
contemplated.
Specific examples of compounds of Formula I are provided below:
TABLE-US-00001 Example Structure Name 1 ##STR00007##
N-Isopropyl-N-[4-(1,1,1-trifluoro-2- hydroxypropan-2-
yl)phenyl]benzenesulfonamide 2 ##STR00008##
2-chloro-N-isopropyl-N-[4-(1,1,1- trifluoro-2-hydroxypropan-2-
yl)phenyl]benzenesulfonamide 2a ##STR00009##
(R)-2-chloro-N-isopropyl-N-[4-(1,1,1- trifluoro-2-hydroxypropan-2-
yl)phenyl]benzenesulfonamide 2b ##STR00010##
(S)-2-chloro-N-isopropyl-N-[4-(1,1,1- trifluoro-2-hydroxypropan-2-
yl)phenyl]benzenesulfonamide 3 ##STR00011##
2,3-dichloro-N-isopropyl-N-[4-(1,1,1- trifluoro-2-hydroxypropan-2-
yl)phenyl]benzenesulfonamide 3a ##STR00012##
(R)-2,3-dichloro-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 3b
##STR00013## (S)-2,3-dichloro-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 4
##STR00014## 2-fluoro-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 5
##STR00015## 2,6-dichloro-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 6
##STR00016## 2-chloro-4-cyano-N-isopropyl-N-[4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 7
##STR00017## 2,5-dichloro-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 7a
##STR00018## (R)-2,5-dichloro-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 7b
##STR00019## (S)-2,5-dichloro-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 8
##STR00020## N-tert-butyl-2,5-dichloro-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 9
##STR00021## 2-chloro-N-(cyclopropylmethyl)-N-[4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 10
##STR00022## 2,5-dichloro-N-isobutyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 11
##STR00023## 2-chloro-N-isopropyl-5-nitro-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 12
##STR00024## 5-amino-2-chloro-N-isopropyl-N-[4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 13
##STR00025## 5-bromo-2-chloro-N-isopropyl-N-[4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 14
##STR00026## chloro-N-ethyl-N-[4-(1,1,1-trifluoro-2-
hydroxypropan-2- yl)phenyl]benzenesulfonamide 15 ##STR00027##
2-chloro-N-methyl-N-[4-(1,1,1-trifluoro- 2-hydroxypropan-2-
yl)phenyl]benzenesulfonamide 16 ##STR00028##
2-chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-
hydroxypropan-2-yl)phenyl)-N- isopropylbenzenesulfonamide 17
##STR00029## 2-chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-
hydroxypropan-2-yl)phenyl)-N- ethylbenzenesulfonamide 18
##STR00030## 2-chloro-N-(1-fluoropropan-2-yl)-N-(4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl)benzenesulfonamide 19
##STR00031## 2,5-dichloro-N-(2,2,2-trifluoroethyl)-N-[4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 20
##STR00032## 2,3-dichloro-N-(2,2,2-trifluoroethyl)-N-[4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 21
##STR00033## 2-chloro-N-(2,2,2-trifluoroethyl)-N-[4-
(1,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 22
##STR00034## 2,3-dichloro-N-cyclopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 23
##STR00035## 2,5-dichloro-N-cyclobutyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 24
##STR00036## 2,5-dichloro-N-phenyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide 25
##STR00037## 2-cyclopropyl-N-isopropyl-N-[4-(1,1,1-
trifluoro-2-hydroxypropan-2- yl)phenyl]benzenesulfonamide
The present invention also provides compositions comprising an
aniline sulfonamide derivative of Formula (I) and a
pharmaceutically acceptable vehicle, carrier, diluent or
excipient.
The invention further provides aniline sulfonamide derivatives of
Formula (I) that are in isolated and purified form.
The invention provides methods for treating diabetes comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
The invention also provides methods for treating obesity comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
The invention further provides methods for treating an HSD-mediated
condition or disorder comprising administering to a patient in need
thereof a therapeutically effective amount of an aniline
sulfonamide derivative of Formula (I).
The invention further provides methods for treating an
11.beta.-HSD1-mediated condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
The invention further provides methods for treating an
11.beta.-HSD2-mediated condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
The invention further provides methods for treating an
17.beta.-HSD3-mediated condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
The invention further provides methods for treating an
HSD-responsive condition or disorder comprising administering to a
patient in need thereof a therapeutically effective amount of an
aniline sulfonamide derivative of Formula (I).
The invention further provides methods for treating an
11.beta.-HSD1-responsive condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
The invention further provides methods for treating an
11.beta.-HSD2-responsive condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
The invention further provides methods for treating an
17.beta.-HSD3-responsive condition or disorder comprising
administering to a patient in need thereof a therapeutically
effective amount of an aniline sulfonamide derivative of Formula
(I).
Preparation of the Aniline Sulfonamide Derivatives of Formula I
Those skilled in the art will recognize that there are a variety of
methods available to synthesize molecules represented in the
claims. In general, useful methods for synthesizing compounds
represented in the claims comprise three parts, which may be done
in any order: Formation of a sulfonamide bond, installation of a
--CR.sup.1R.sup.2R.sup.3 group, and installation or modification of
functional groups appended to the --N(LR.sup.5)SO.sub.2R.sup.6
group and the R.sup.4-substituted aryl ring. Retrosynthetic
disconnection of the compounds of the invention into fragments a, b
and c, useful for construction of the compounds, is shown
below:
##STR00038##
Various methods can be employed to prepare the compounds of this
invention (eq. 1-4). Equation one demonstrates one method of
forming the sulfonamide linkage. In the case of eq. 1, X may be
chosen from an appropriate group such as Cl or F, or from any group
capable of activating a sulfonyl group for displacement by an amine
(e.g., imidazole, etc.).
##STR00039##
The coupling referred to in eq. 1 can be assisted by the use of
organic or inorganic bases, and also by catalysts, such as DMAP and
the like. Suitable coupling partners include but are not limited to
a sulfonyl chloride and an amine, a sulfonyl fluoride and an amine,
RSO.sub.2-imidazole and an amine. Those skilled in the art will
recognize that there are other possible combinations which will
also result in the desired product.
The installation of L-R.sup.5 can be accomplished prior to
formation of the sulfonamide linkage (eq. 1) or after sulfonamide
formation (eq.2). In the latter case, alkylation of the sulfonamide
nitrogen can be accomplished using general methods known to those
skilled in the art, where X is a halide, triflate, or other group
suitable for nucleophilic displacement. The reactions in eq. 2 can
be assisted by the use of organic or inorganic bases.
##STR00040##
Installation of the --CR.sup.1R.sup.2R.sup.3 group can occur before
or after the central coupling reaction, and can be further modified
at various times during the preparation of the claimed molecules.
Equation 3 demonstrates one method in which the
--CR.sup.1R.sup.2R.sup.3 group is installed in the form of a ketone
before the central coupling reaction, followed by further
modification to reach compounds of the invention. Following the
central coupling, addition of a nucleophile ("Nu") such as
CF.sub.3.sup.- or CH.sub.3.sup.- via addition of; e.g.,
CF.sub.3TMS, MeLi, MeMgBr or similar reagent, completes the
installation of the --CR.sup.1R.sup.2R.sup.3 group. This can be
followed by further modification of substituents to complete the
preparation.
##STR00041##
Alternatively, the --CR.sup.1R.sup.2R.sup.3 group can be installed
following the central coupling via Friedel-Crafts acylation, as
shown in eq. 4. Those skilled in the art will understand that this
methodology may particularly accommodate some substitution
patterns. Further modification as in equations 1, 2, and 3 provides
the compounds of the invention.
##STR00042##
Introduction of the trifluoromethyl carbinol moiety can be achieved
via a variety of methods, some of which are exemplified in
equations 5-7. The --CF.sub.3 group can be introduced by addition
to a ketone using CF.sub.3TMS and TBAF, or the quaternary ammonium
base of TBAF can be substituted with a chiral quaternary base, such
as in equation 5, to produce, for example, one enantiomer in
excess, such as is described in Caron et al. (2003) Synthesis
1693-1698.
##STR00043##
Another useful method is the chiral addition of a nucleophile such
as MeLi or MeMgBr mediated via an amine or aminoalcohol additive
(eq. 6) to a trifluoromethylketone (for an example, see Thompson et
al. (1995) Tetrahedron Lett. 49:8937-8940). Yet another useful
method is Friedel-Crafts alkylation (eq. 7), which may be done in a
fashion to give optically active products using chiral catalysts
such as binaphthol derived titanium catalysts (Ishii et al. (2000)
J. Org. Chem 65:1597-1599), and chiral copper catalysts (Zhuang et
al. (2001) J. Org. Chem. 66:1009-1013). One skilled in the art will
understand that a variety of methods are available for this
transformation. For the most efficient preparation of any
particular compound of the invention, one skilled in the art will
recognize that the timing of the introduction of the
--CR.sup.1R.sup.2R.sup.3 group can vary, and may be the first,
last, or intermediate transformation in the preparation of a given
compound.
A variety of the methods described above were used to prepare
compounds of the invention, some of which are shown in the
examples.
Pharmaceutical Compositions
Pharmaceutical compositions and single unit dosage forms comprising
an aniline sulfonamide derivative, or a pharmaceutically acceptable
stereoisomer, prodrug, salt, solvate, hydrate, or clathrate
thereof, are also encompassed by the invention. Individual dosage
forms of the invention may be suitable for oral, mucosal (including
sublingual, buccal, rectal, nasal, or vaginal), parenteral
(including subcutaneous, intramuscular, bolus injection,
intraarterial, or intravenous), transdermal, or topical
administration.
Examples of dosage forms include, but are not limited to: tablets;
caplets; capsules, such as soft elastic gelatin capsules; cachets;
troches; lozenges; dispersions; suppositories; ointments;
cataplasms (poultices); pastes; powders; dressings; creams;
plasters; solutions; patches; aerosols (e.g., nasal sprays or
inhalers); gels; liquid dosage forms suitable for oral or mucosal
administration to a patient, including suspensions (e.g., aqueous
or non-aqueous liquid suspensions, oil-in-water emulsions, or a
water-in-oil liquid emulsions), solutions, effervescent
compositions, and elixirs; liquid dosage forms suitable for
parenteral administration to a patient; and sterile solids (e.g.,
crystalline or amorphous solids) that can be reconstituted to
provide liquid dosage forms suitable for parenteral administration
to a patient.
The composition, shape, and type of dosage forms of the invention
will typically vary depending on their use. For example, a dosage
form used in the acute treatment of inflammation or a related
disease may contain larger amounts of one or more of the active
ingredients it comprises than a dosage form used in the chronic
treatment of the same disease. Similarly, a parenteral dosage form
may contain smaller amounts of one or more of the active
ingredients it comprises than an oral dosage form used to treat the
same disease or disorder. These and other ways in which specific
dosage forms encompassed by this invention will vary from one
another will be readily apparent to those skilled in the art. See,
e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing, Easton Pa. (1990).
Typical pharmaceutical compositions and dosage forms comprise one
or more carriers, excipients or diluents. Suitable excipients are
well known to those skilled in the art of pharmacy, and
non-limiting examples of suitable excipients are provided herein.
Whether a particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form depends on a variety of
factors well known in the art including, but not limited to, the
way in which the dosage form will be administered to a patient. For
example, oral dosage forms such as tablets may contain excipients
not suited for use in parenteral dosage forms. The suitability of a
particular excipient may also depend on the specific active
ingredients in the dosage form.
This invention further encompasses anhydrous (e.g., <1% water)
pharmaceutical compositions and dosage forms comprising active
ingredients, since water can facilitate the degradation of some
compounds. For example, the addition of water (e.g., 5%) is widely
accepted in the pharmaceutical arts as a means of simulating
long-term storage in order to determine characteristics such as
shelf-life or the stability of formulations over time. See, e.g.,
Jens T. Carstensen, Drug Stability: Principles & Practice, 2d.
Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water
and heat accelerate the decomposition of some compounds. Thus, the
effect of water on a formulation can be of great significance since
moisture and/or humidity are commonly encountered during
manufacture, handling, packaging, storage, shipment, and use of
formulations.
Anhydrous pharmaceutical compositions and dosage forms of the
invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine can be anhydrous if substantial contact with
moisture and/or humidity during manufacturing, packaging, and/or
storage is expected.
An anhydrous pharmaceutical composition should be prepared and
stored such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions can be packaged using materials known to
prevent exposure to water such that they can be included in
suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastics, unit
dose containers (e.g., vials), blister packs, and strip packs.
The invention further encompasses pharmaceutical compositions and
dosage forms that comprise one or more compounds that reduce the
rate by which an active ingredient will decompose. Such compounds,
which are referred to herein as "stabilizers," include, but are not
limited to, antioxidants such as ascorbic acid, pH buffers, or salt
buffers.
The aniline sulfonamide derivatives of formula I can be
administered to a mammal (human, horse, mouse, rat, rabbit, dog,
cat, bovine, pig, monkey etc.) as an 11.beta.-HSD1 modulator, a
prophylactic or therapeutic drug of diabetes, a prophylactic or
therapeutic drug of diabetic complication (retinopathy,
nephropathy, neuropathy, cardiac infarction and cerebral infarction
based on arteriosclerosis etc.), a prophylactic or therapeutic drug
of hyperlipemia, a prophylactic or therapeutic drug of obesity,
neurodegenerative disease and the like, or a prophylactic or
therapeutic drug of diseases mediated by 11.beta.-HSD1.
The aniline sulfonamide derivatives can be administered to a mammal
concurrently with an additional therapeutic agent for the treatment
of a disease, such as diabetes or obesity, with the aim of the
prophylaxis or treatment of a disease. As such, the aniline
sulfonamide derivatives of the present invention can be
administered in combination with other therapeutic agents for the
treatment or prevention of numerous diseases, including, but not
limited to, diabetes and obesity.
Depending on the disease to be treated and the patient's condition,
the compounds of the invention may be administered by oral,
parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,
intracisternal injection or infusion, subcutaneous injection or
implant), inhalation, nasal, vaginal, rectal, sublingual, or
topical (e.g., transdermal, local) routes of administration and may
be formulated, alone or together, in suitable dosage unit
formulations containing conventional non-toxic pharmaceutically
acceptable carriers, adjuvants and vehicles appropriate for each
route of administration. The invention also contemplates
administration of the compounds of the invention in a depot
formulation, in which the active ingredient is released over a
defined time period.
In the case of a combined administration, the aniline sulfonamide
derivatives may be administered simultaneously with other another
therapeutic agent that is useful for the treatment or prevention of
diabetes, obesity or other disease or may be administered at a time
prior to or subsequent to another therapeutic agent. In the case of
combined administration, a pharmaceutical composition containing
the aniline sulfonamide derivative and an additional therapeutic
agent can be administered. Alternatively, a pharmaceutical
composition containing the aniline sulfonamide derivative and a
pharmaceutical composition containing an additional therapeutic
agent may be administered separately. The administration routes of
respective pharmaceutical compositions may be the same or
different.
In the case of a combined administration, the aniline sulfonamide
derivatives may be administered at a dose of 50 mg to 800 mg per
administration, which is given up to several times a day. For
example, dosing of once per day or less than once per day is
contemplated. In addition, the compound may be administered at a
smaller dose. The combined pharmaceutical agent can be administered
at a dose generally employed for the prophylaxis or treatment of
diabetes or obesity or at a smaller dose than that.
Like the amounts and types of excipients, the amounts and specific
types of active ingredients in a dosage form may differ depending
on factors such as, but not limited to, the route by which it is to
be administered to patients. However, typical dosage forms of the
invention comprise an aniline sulfonamide derivative, or a
pharmaceutically acceptable salt, solvate, clathrate, hydrate,
polymoprh or prodrug thereof. In the treatment or prevention of
diabetes, obesity, glaucoma, osteoporosis, cognitive disorders,
immune disorders, depression or other conditions or disorders
associated with the modulation of an hydroxysteroid dehydrogenase,
an appropriate dosage level will generally be from about 0.001 to
about 100 mg per kg patient body weight per day which can be
administered in single or multiple doses. An exemplary dosage level
can be from about 0.01 to about 25 mg/kg per day or about 0.05 to
about 10 mg/kg per day. In other embodiments, a suitable dosage
level can be from about 0.01 to about 25 mg/kg per day, about 0.05
to about 10 mg/kg per day, or about 0.1 to about 5 mg/kg per day.
Within this range the dosage can be from about 0.005 to about 0.05,
about 0.05 to about 0.5 or about 0.5 to about 5.0 mg/kg per day lie
within the range of from about 0.1 mg to about 2000 mg per day,
given as a single once-a-day dose in the morning but typically as
divided doses throughout the day taken with food. In one
embodiment, the daily dose is administered twice daily in equally
divided doses. A daily dose range can be from about 5 mg to about
500 mg per day or between about 10 mg and about 200 mg per day. In
managing the patient, the therapy can be initiated at a lower dose,
such as from about 1 mg to about 25 mg, and increased if necessary
up to from about 200 mg to about 2000 mg per day as either a single
dose or divided doses, depending on the patient's global
response.
For multidrug therapy, the weight ratio of the compound of the
invention to the second active ingredient may be varied and will
depend upon the effective dose of each ingredient. Generally, an
effective dose of each will be used. Thus, for example, when a
compound of the invention is combined with an NSAID, the weight
ratio of the compound of the invention to the NSAID will generally
range from about 1000:1 to about 1:1000, such as from about 200:1
to about 1:200. Combinations of a compound of the invention and
other active ingredients will generally also be within the
aforementioned range, but in each case, an effective dose of each
active ingredient should be used.
It will be understood, however, that the specific dose level and
frequency of dosage for any particular patient may be varied and
will depend upon a variety of factors including the activity of the
specific compound employed, the metabolic stability and length of
action of that compound, the age, body weight, general health, sex,
diet, mode and time of administration, rate of excretion, drug
combination, the severity of the particular condition, and the host
undergoing therapy.
Oral Dosage Forms
Pharmaceutical compositions of the invention that are suitable for
oral administration can be presented as discrete dosage forms, such
as, but are not limited to, tablets (e.g., chewable tablets),
caplets, capsules, and liquids (e.g., flavored syrups). Such dosage
forms contain predetermined amounts of active ingredients, and may
be prepared by methods of pharmacy well known to those skilled in
the art. See generally, Remington's Pharmaceutical Sciences, 18th
ed., Mack Publishing, Easton Pa. (1990).
Typical oral dosage forms of the invention are prepared by
combining the active ingredient(s) in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
Because of their ease of administration, tablets and capsules
represent the most advantageous oral dosage unit forms, in which
case solid excipients are employed. If desired, tablets can be
coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
For example, a tablet can be prepared by compression or molding.
Compressed tablets can be prepared by compressing in a suitable
machine the active ingredients in a free-flowing form such as
powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the
invention include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
Suitable forms of microcrystalline cellulose include, but are not
limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103
AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation,
American Viscose Division, Avicel Sales, Marcus Hook, PA), and
mixtures thereof. An specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM.
Disintegrants are used in the compositions of the invention to
provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
specifically from about 1 to about 5 weight percent of
disintegrant.
Disintegrants that can be used in pharmaceutical compositions and
dosage forms of the invention include, but are not limited to,
agar-agar, alginic acid, calcium carbonate, microcrystalline
cellulose, croscarmellose sodium, crospovidone, polacrilin
potassium, sodium starch glycolate, potato or tapioca starch,
pre-gelatinized starch, other starches, clays, other algins, other
celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and
dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
For oral administration, the compositions can be provided in the
form of tablets containing about 1 to about 1000 milligrams of the
active ingredient. In other embodiments, the compositions are
provided in provided in the form of tablets containing about 1.0,
about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about
50.0, about 75.0, about 100.0, about 150.0, about 200.0, about
250.0, about 300.0, about 400.0, about 500.0, about 600.0, about
750.0, about 800.0, about 900.0, or about 1000.0 milligrams of the
active ingredient for the symptomatic adjustment of the dosage to
the patient to be treated. The compounds may be administered on a
regimen of 1 to 4 times per day, such as once or twice per day.
Delayed Release Dosage Forms
Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
Controlled-release pharmaceutical products can improve drug therapy
over that achieved by their non-controlled counterparts. Ideally,
the use of an optimally designed controlled-release preparation in
medical treatment is characterized by a minimum of drug substance
being employed to cure or control the condition in a minimum amount
of time. Advantages of controlled-release formulations include
extended activity of the drug, reduced dosage frequency, and
increased patient compliance. In addition, controlled-release
formulations can be used to affect the time of onset of action or
other characteristics, such as blood levels of the drug, and can
thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are designed to initially
release an amount of drug (active ingredient) that promptly
produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various
routes including, but not limited to, subcutaneous, intravenous
(including bolus injection), intramuscular, and intra-arterial.
Because their administration typically bypasses patients' natural
defenses against contaminants, parenteral dosage forms can be
sterile or capable of being sterilized prior to administration to a
patient. Examples of parenteral dosage forms include, but are not
limited to, solutions ready for injection, dry products ready to be
dissolved or suspended in a pharmaceutically acceptable vehicle for
injection, suspensions ready for injection, and emulsions. For
example, lyophilized sterile compositions suitable for
reconstitution into particulate-free dosage forms suitable for
administration to humans.
Suitable vehicles that can be used to provide parenteral dosage
forms of the invention are well known to those skilled in the art.
Examples include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous
vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
Compounds that increase the solubility of one or more of the active
ingredients disclosed herein can also be incorporated into the
parenteral dosage forms of the invention.
In some embodiments, parenteral dosage forms used for the methods
of preventing, treating or managing disease in a cancer
patient.
Transdermal and Topical Dosage Forms
Transdermal and topical dosage forms of the invention include, but
are not limited to, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., Remington's Pharmaceutical Sciences, 18th eds.,
Mack Publishing, Easton Pa. (1990); and Introduction to
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,
Philadelphia (1985). Transdermal dosage forms include "reservoir
type" or "matrix type" patches, which can be applied to the skin
and worn for a specific period of time to permit the penetration of
a desired amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal and topical
dosage forms encompassed by this invention are well known to those
skilled in the pharmaceutical arts, and depend on the particular
tissue to which a given pharmaceutical composition or dosage form
will be applied. With that fact in mind, typical excipients
include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,
isopropyl palmitate, mineral oil, and mixtures thereof to form
lotions, tinctures, creams, emulsions, gels or ointments, which are
non-toxic and pharmaceutically acceptable. Moisturizers or
humectants also can be added to pharmaceutical compositions and
dosage forms if desired. Examples of such additional ingredients
are well known in the art. See, e.g., Remington's Pharmaceutical
Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).
Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various
water-soluble or insoluble sugar esters such as Tween 80
(polysorbate 80) and Span 60 (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the
tissue to which the pharmaceutical composition or dosage form is
applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
Mucosal Dosage Forms and Lung Delivery
Mucosal dosage forms of the invention include, but are not limited
to, ophthalmic solutions, sprays and aerosols, or other forms known
to one of skill in the art. See, e.g., Remington's Pharmaceutical
Sciences, 18th eds., Mack Publishing, Easton Pa. (1990); and
Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea &
Febiger, Philadelphia (1985). Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels. In one embodiment, the aerosol
comprises a carrier. In another embodiment, the aerosol is carrier
free.
A compound of the invention can also be administered directly to
the lung by inhalation (see e.g., Tong et al., International
Publication. No. WO 97/39745; Clark et al, International
Publication No. WO 99/47196, which are herein incorporated by
reference). For administration by inhalation, an aniline
sulfonamide derivative can be conveniently delivered to the lung by
a number of different devices. For example, a Metered Dose Inhaler
("MDI") which utilizes canisters that contain a suitable low
boiling propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas can be used to deliver an aniline sulfonamide
derivative directly to the lung. MDI devices are available from a
number of suppliers such as 3M Corporation, Aventis, Boehringer
Ingleheim, Forest Laboratories, Glaxo-Wellcome, Schering Plough and
Vectura.
Alternatively, a Dry Powder Inhaler (DPI) device can be used to
administer an aniline sulfonamide derivative to the lung (See,
e.g., Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual
Meeting, 1999, 40, 397, which is herein incorporated by reference).
DPI devices typically use a mechanism such as a burst of gas to
create a cloud of dry powder inside a container, which can then be
inhaled by the patient. DPI devices are also well known in the art
and can be purchased from a number of vendors which include, for
example, Fisons, Glaxo-Wellcome, Inhale Therapeutic Systems, ML
Laboratories, Qdose and Vectura. A popular variation is the
multiple dose DPI ("MDDPI") system, which allows for the delivery
of more than one therapeutic dose. MDDPI devices are available from
companies such as AstraZeneca, GlaxoWellcome, IVAX, Schering
Plough, SkyePharma and Vectura. For example, capsules and
cartridges of gelatin for use in an inhaler or insufflator can be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch for these systems.
Another type of device that can be used to deliver an aniline
sulfonamide derivative to the lung is a liquid spray device
supplied, for example, by Aradigm Corporation. Liquid spray systems
use extremely small nozzle holes to aerosolize liquid drug
formulations that can then be directly inhaled into the lung.
In one embodiment, a nebulizer device is used to deliver an aniline
sulfonamide derivative to the lung. Nebulizers create aerosols from
liquid drug formulations by using, for example, ultrasonic energy
to form fine particles that can be readily inhaled (See e.g.,
Verschoyle et al., British J Cancer, 1999, 80, Suppl 2, 96, which
is herein incorporated by reference). Examples of nebulizers
include devices supplied by Sheffield/Systemic Pulmonary Delivery
Ltd. (See, Armer et al., U.S. Pat. No. 5,954,047; van der Linden et
al., U.S. Pat. No. 5,950,619; van der Linden et al., U.S. Pat. No.
5,970,974, which are herein incorporated by reference), Aventis and
Batelle Pulmonary Therapeutics. Inhaled compounds, delivered by
nebulizer devices, are currently under investigation as treatments
for aerodigestive cancer (Engelke et al., Poster 342 at American
Association of Cancer Research, San Francisco, Calif., Apr. 1-5,
2000) and lung cancer (Dahl et al., Poster 524 at American
Association of Cancer Research, San Francisco, Calif., Apr. 1-5,
2000).
In another embodiment, an electrohydrodynamic ("EHD") aerosol
device is used to deliver an aniline sulfonamide derivative to the
lung. EHD aerosol devices use electrical energy to aerosolize
liquid drug solutions or suspensions (see e.g., Noakes et al., U.S.
Pat. No. 4,765,539; Coffee, U.S. Pat. No., 4,962,885; Coffee,
International Publication No. WO 94/12285; Coffee, International
Publication No. WO 94/14543; Coffee, International Publication No.
WO 95/26234, Coffee, International Publication No. WO 95/26235,
Coffee, International Publication No. WO 95/32807, which are herein
incorporated by reference). The electrochemical properties of the
compound of the invention formulation may be important parameters
to optimize when delivering this drug to the lung with an EHD
aerosol device and such optimization is routinely performed by one
of skill in the art. EHD aerosol devices may more efficiently
delivery drugs to the lung than existing pulmonary delivery
technologies. Other methods of intra-pulmonary delivery of an
aniline sulfonamide derivative will be known to the skilled artisan
and are within the scope of the invention.
Liquid drug formulations suitable for use with nebulizers and
liquid spray devices and EHD aerosol devices will typically include
an aniline sulfonamide derivative with a pharmaceutically
acceptable carrier. In some embodiments, the pharmaceutically
acceptable carrier is a liquid such as alcohol, water, polyethylene
glycol or a perfluorocarbon. Optionally, another material may be
added to alter the aerosol properties of the solution or suspension
of an aniline sulfonamide derivative. This material can be a liquid
such as an alcohol, glycol, polyglycol or a fatty acid. Other
methods of formulating liquid drug solutions or suspension suitable
for use in aerosol devices are known to those of skill in the art
(See, e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S.
Pat. No. 5,556,611, which are herein incorporated by reference). A
compound of the invention can also be formulated in rectal or
vaginal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
In addition to the formulations described previously, an aniline
sulfonamide derivative can also be formulated as a depot
preparation. Such long acting formulations can be administered by
implantation (for example subcutaneously or intramuscularly) or by
intramuscular injection. Thus, for example, the compounds can be
formulated with suitable polymeric or hydrophobic materials (for
example, as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
Other Delivery Systems
Alternatively, other pharmaceutical delivery systems can be
employed. Liposomes and emulsions are well known examples of
delivery vehicles that can be used to deliver an aniline
sulfonamide derivative. Certain organic solvents such as
dimethylsulfoxide can also be employed, although usually at the
cost of greater toxicity. A compound of the invention can also be
delivered in a controlled release system. In one embodiment, a pump
can be used (Sefton, CRC Crit. Ref Biomed Eng., 1987, 14, 201;
Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., N. Engl. J
Med, 1989, 321, 574). In another embodiment, polymeric materials
can be used (see Medical Applications of Controlled Release, Langer
and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled
Drug Bioavailability, Drug Product Design and Performance, Smolen
and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J
Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see also Levy et
al., Science 1985, 228, 190; During et al., Ann. Neurol.,
1989,25,351; Howard et al., 1989, J. Neurosurg. 71, 105). In yet
another embodiment, a controlled-release system can be placed in
proximity of the target of the compounds of the invention, e.g.,
the lung, thus requiring only a fraction of the systemic dose (see,
e.g., Goodson, in Medical Applications of Controlled Release,
supra, vol. 2, pp. 115 (1984)). Other controlled-release system can
be used (see e.g., Langer, Science, 1990, 249, 1527).
Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide mucosal dosage forms
encompassed by this invention are well known to those skilled in
the pharmaceutical arts, and depend on the particular site or
method which a given pharmaceutical composition or dosage form will
be administered. With that fact in mind, typical excipients
include, but are not limited to, water, ethanol, ethylene glycol,
propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl
palmitate, mineral oil, and mixtures thereof, which are non-toxic
and pharmaceutically acceptable. Examples of such additional
ingredients are well known in the art. See, e.g., Remington's
Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa.
(1990).
The pH of a pharmaceutical composition or dosage form, or of the
tissue to which the pharmaceutical composition or dosage form is
applied, can also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
Therapeutic Uses Of The Aniline Sulfonamide Derivatives
In one aspect, the invention provides methods of treating or
preventing a condition or disorder associated with the modulation
of hydroxysteroid dehydrogenases by administering to a patient
having such a condition or disorder a therapeutically effective
amount of a compound or composition of the invention. In one group
of embodiments, conditions and disorders, including chronic
diseases of humans or other species, can be treated with
modulators, stimulators, or inhibitors of hydroxysteroid
dehydrogenases, such as 11.beta.-HSD1.
Treatment or Prevention of Diabetes
Diabetes and diabetic conditions can be treated or prevented by
administration of a therapeutically effective amount of an aniline
sulfonamide derivative.
Types of diabetes that can be treated or prevented by administering
a therapeutically effective amount of an aniline sulfonamide
derivative include type I diabetes mellitus juvenile onset
diabetes, insulin dependent-diabetes mellitus or IDDM), type II
diabetes mellitus (non-insulin-dependent diabetes mellitus or
NIDDM), insulinopathies, diabetes associated with pancreatic
disorders, diabetes associated with other disorders (such as
Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma,
primary aldosteronism, and somatostatinoma), type A and type B
insulin resistance syndromes, lipatrophic diabetes, and diabetes
induced by .beta.-cell toxins.
In some embodiments, the type of diabetes being treated is type II
diabetes.
Treatment or Prevention of Obesity
Obesity can be treated or prevented by administration of a
therapeutically effective amount of an aniline sulfonamide
derivative.
Obesity may have genetic, environmental (e.g., expending less
energy than is consumed) and regulatory determinants. Obesity
includes exogenous, hyperinsulinar, hyperplasmic, hypothyroid,
hypothalamic, symptomatic, infantile, upper body, alimentary,
hypogonadal, simple and central obesity, hypophyseal adiposity and
hyperphagia. Metabolic disorders, such as hyperlidemia and
diabetes, and cardiovascular disorders, such as hypertension and
coronary artery disease, are commonly associated with obesity.
Complications due to obesity may also be treated or prevented by
administering a therapeutically effective amount of an aniline
sulfonamide derivative. Such complications include, but are not
limited to, sleep apnea, Pickwickian syndrome, orthopedic
disturbances of weight-bearing and non-weight-bearing joints, and
skin disorders resulting from increased sweat or skin
secretions.
Treatment or Prevention of Other Conditions
Other conditions that can be treated or prevented by administering
a therapeutically effective amount of an aniline sulfonamide
derivative include, but are not limited to any condition which is
responsive to the modulation, such as inhibition, of hydroxysteroid
dehydrogenases or specific isoforms thereof, and thereby benefit
from administration of such a modulator. Representative conditions
in this regard include, but are not limited to, metabolic disorders
and related cardiovascular risk factors such as syndrome X,
polycystic ovarian disease, eating disorders (e.g., anorexia and
bulimia), craniopharyngioma, Prader-Willi syndrome, Frohlich's
syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia,
hypertriglyceridemia, low HDL levels, high HDL levels,
hyperglycemia, insulin resistance, hyperinsulinemia and Cushing's
syndrome; diseases associated therewith such as hypertension,
atherosclerosis, vascular restenosis, retinopathy and nephropathy;
neurologic disorders such as neurodegenerative disease, neuropathy
and muscle wasting; cognitive disorders, such as age-related
learning disorders, dementia, neurodegeneration, as well as for
improvement of cognitive function in subjects ranging from the
severely impaired (e.g., Parkinsons's or Alzheimer's associated
dementia) to mildly impaired (e.g., age-associated memory
impairment, drug-induced cognitive impairment) to unimpaired
subjects (e.g., cognitive enhancers for the general population)
(see, Sandeep, et al., PNAS, electronically available at
www.pnas.org/cgi/doi/10.1073/pnas.0306996101); androgen and/or
estrogen-related disorders such as prostate cancer, colon cancer,
breast cancer, benign prostatic hyperplasia, ovarian cancer,
uterine cancer, and male pseudohermaphrodism; endometriosis,
dementia, depression, psoriasis, glaucoma, osteoporosis, viral
infections, inflammatory disorders, and immune disorders.
Additional Therapeutic Agents
In one embodiment, the present methods for treating or preventing
further comprise the administration of a therapeutically effective
amount of another therapeutic agent useful for treating or
preventing the diseases or disorders disclosed herein. In this
embodiment, the time in which the therapeutic effect of the other
therapeutic agent is exerted overlaps with the time in which the
therapeutic effect of the aniline sulfonamide derivative is
exerted.
The compounds of the invention can be combined or used in
combination with other agents useful in the treatment, prevention,
suppression or amelioration of the conditions or disorders for
which compounds of the invention are useful, including diabetes,
obesity, glaucoma, osteoporosis, cognitive disorders, immune
disorders, depression and those pathologies noted above.
Such other agents, or drugs, can be administered, by a route and in
an amount commonly used therefor, simultaneously or sequentially
with an aniline sulfonamide derivative. In one embodiment, a
pharmaceutical composition contains such other drugs in addition to
the compound of the invention when an aniline sulfonamide
derivative is used contemporaneously with one or more other drugs.
Accordingly, the pharmaceutical compositions of the invention
include those that also contain one or more other active
ingredients or therapeutic agents, in addition to an aniline
sulfonamide derivative.
In one embodiment, for the treatment or prevention of diabetes, an
aniline sulfonamide derivative can be administered with another
therapeutic agent, including, but not limited to, anti-diabetic
agents such as insulin, inhaled insulin (Exubera.RTM.), insulin
mimetics, insulin secretogues, sulfonylureas (e.g., glyburide,
meglinatide, glimepiride, gliclazide, glipizide, gliquidone,
chloropropresponsivemide, tolbutamide, acetohexamide,
glycopyramide, carbutamide, glibonuride, glisoxepid, glybuthiazole,
glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide,
tolcylamide and tolazamide), biguanides (e.g., metformin
(Glucophage.RTM.)), .alpha.-glucosidase inhibitors (e.g., acarbose,
voglibose and miglitol), thiazolidinone compounds (e.g.,
rosiglitazone (Avandia.RTM.), troglitazone (Rezulin.RTM.),
ciglitazone, pioglitazone (Actos.RTM.) and englitazone), prandial
glucose regulators (e.g., repaglinide and nateglinide) and glucagon
receptor antagonists.
In another embodiment, for the treatment or prevention of obesity,
an aniline sulfonamide derivative can be administered with another
therapeutic agent, including, but not limited to, .beta.3
adrenergic receptor agonists, leptin or derivatives thereof,
neuropeptide Y (e.g., NPY5) antagonists, and mazindol.
Examples of other therapeutic agents that may be combined with an
aniline sulfonamide derivative, either administered separately or
in the same pharmaceutical compositions, include, but are not
limited to: (i) cholesterol lowering agents such as HMG-CoA
reductase inhibitors (e.g., lovastatin, simvastatin (Zocor.RTM.),
pravastatin, fluvastatin, atorvastatin (Lipitor.RTM.) and other
statins), bile acid sequestrants (e.g., cholestyramine and
colestipol), vitamin B.sub.3 (also known as nicotinic acid, or
niacin), vitamin B.sub.6 (pyridoxine), vitamin B.sub.12
(cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil,
clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin,
and inhibitors of cholesterol absorption (e.g., beta-sitosterol and
acylCoA-cholesterol acyltransferase (ACAT) inhibitors such as
melinamide), HMG-CoA synthase inhibitors, squalene epoxidase
inhibitors and squalene synthetase inhibitors; (ii) antithrombotic
agents, such as thrombolytic agents (e.g., streptokinase,
alteplase, anistreplase and reteplase), heparin, hirudin and
warfarin derivatives, .beta.-blockers (e.g., atenolol), .beta.
adrenergic agonists (e.g., isoproterenol), angiotensin II
antagonists, ACE inhibitors and vasodilators (e.g., sodium
nitroprusside, nicardipine hydrochloride, nitroglycerin and
enaloprilat); (iii) PPAR agonists, e.g., PPAR.gamma. and
PPAR.delta. agonists; (iv) DP antagonists; (v) lubricants or
emollients such as petrolatum and lanolin, keratolytic agents,
vitamin D.sub.3 derivatives (e.g., calcipotriene and calcipotriol
(Dovonex.RTM.)), PUVA, anthralin (Drithrocreme.RTM.), etretinate
(Tegison.RTM.) and isotretinoin; (vi) glaucoma therapies such as
cholinergic agonists (e.g., pilocarpine and carbachol),
cholinesterase inhibitors (e.g., physostigmine, neostigmine,
demacarium, echothiophate iodide and isofluorophate), carbonic
anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide,
methazolamide, ethoxzolamide and dorzolamide), non-selective
adrenergic agonists (e.g., epinephrine and dipivefrin),
.alpha..sub.2-selecteive adrenergic agonists (e.g., apraclonidine
and brimonidine), .beta.-blockers (e.g., timolol, betazolol,
levobunolol, carteolol and metipranolol), prostaglandin analogs
(e.g., latanoprost) and osmotic diuretics (e.g., glycerin, mannitol
and isosorbide); corticosteroids, such as beclomethasone,
methylprednisolone, betamethasone, prednisone, prenisolone,
dexamethasone, fluticasone and hydrocortisone, and corticosteroid
analogs such as budesonide; (vii) immunosuppressants such as
cyclosporine (cyclosporine A, Sandimmune.RTM., Neoral.RTM.),
tacrolimus (FK-506, Prograf.RTM.), rapamycin (sirolimus,
Rapamune.RTM.) and other FK-506 type immunosuppressants, and
mycophenolate, e.g., mycophenolate mofetil (CellCept.RTM.); (viii)
non-steroidal antiinflammatory agents (NSAIDs) such as propionic
acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,
carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,
ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,
pirprofen, pranoprofen, suprofen, tiaprofenic acid and
tioxaprofen), acetic acid derivatives (e.g., indomethacin,
acemetacin, alclofenac, clidanac, diclofenac, fenclofenac,
fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac,
sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic
acid derivatives (e.g., flufenamic acid, meclofenamic acid,
mefenamic acid, niflumic acid and tolfenamic acid),
biphenylcarboxylic acid derivatives (e.g., diflunisal and
flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam and
tenoxican), salicylates (e.g., acetylsalicylic acid and
sulfasalazine) and the pyrazolones (e.g., apazone, bezpiperylon,
feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); (ix)
cyclooxygenase-2 (COX-2) inhibitors such as celecoxib
(Celebrex.RTM.) and rofecoxib (Vioxx.RTM.); (xi) inhibitors of
phosphodiesterase type IV (PDE-IV); (xii) opioid analgesics such as
codeine, fentanyl, hydromorphone, levorphanol, meperidine,
methadone, morphine, oxycodone, oxymorphone, propoxyphene,
buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine;
(xiii) a hepatoprotective agent; and (xiv) other compounds such as
5-aminosalicylic acid and prodrugs thereof.
The weight ratio of the compound of the invention to the second
active ingredient may be varied and will depend upon the effective
dose of each ingredient. Generally, an effective dose of each will
be used. Thus, for example, when an aniline sulfonamide derivative
is combined with an NSAID, the weight ratio of the compound of the
invention to the NSAID will generally range from about 1000:1 to
about 1:1000, such as about 200:1 to about 1:200. Combinations of
an aniline sulfonamide derivative and other active ingredients will
generally also be within the aforementioned range, but in each
case, an effective dose of each active ingredient should be
used.
Kits
The invention encompasses kits that can simplify the administration
of the aniline sulfonamide derivatives or composition of the
invention to a patient.
A typical kit of the invention comprises a unit dosage of an
aniline sulfonamide derivative. In one embodiment, the unit dosage
form is in a container, which can be sterile, containing a
therapeutically effective amount of an aniline sulfonamide
derivative and a pharmaceutically acceptable vehicle. In another
embodiment, the unit dosage form is in a container containing a
therapeutically effective amount of an aniline sulfonamide
derivative as a lyophilate or pharmaceutically acceptable salt. In
this instance, the kit can further comprise another container that
contains a solution useful for the reconstitution of the lyophilate
or dissolution of the salt. The kit can also comprise a label or
printed instructions for use of the aniline sulfonamide
derivatives.
The kits fo the instant invention may also comprise a second
therapeutic agent that can be administered sequentially,
separately, or concomitantly. Non-limiting examples of such second
therapeutic agents are described hereinabove.
In a further embodiment, the kit comprises a unit dosage form of a
composition of the invention.
Kits of the invention can further comprise one or more devices that
are useful for administering the unit dosage forms of the aniline
sulfonamide derivatives or a composition of the invention. Examples
of such devices include, but are not limited to, a syringe, a drip
bag, a patch or an enema, which optionally contain the unit dosage
forms.
*****
The present invention is not to be limited in scope by the specific
embodiments disclosed in the examples which are intended as
illustrations of a few aspects of the invention and any embodiments
that are functionally equivalent are within the scope of this
invention. Indeed, various modifications of the invention in
addition to those shown and described herein will become apparent
to those skilled in the art and are intended to fall within the
scope of the appended claims. To this end, it should be noted that
one or more hydrogen atoms or methyl groups may be omitted from the
drawn structures consistent with accepted shorthand notation of
such organic compounds, and that one skilled in the art of organic
chemistry would readily appreciate their presence.
EXAMPLES
The aniline sulfonamide derivatives represented by the formulas of
the present invention and the methods of making thereof are
explained in detail in the following Examples, which are not to be
construed as limiting the invention.
Example 1
Preparation of
N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzenesulf-
onamide (1)
##STR00044##
(a) 1,1,1-Trifluoro-2-(4-nitrophenyl)propan-2-ol. A solution of
4'-nitroacetophenone (15.0 g, 90.8 mmol, 1.0 equiv) and
TMS-CF.sub.3 (39.9 mL, 272 mmol, 3.0 equiv) in THF (150 mL) was
treated at 0.degree. C. with tetrabutylammonium fluoride (45.0 mL,
1.0 M in THF, 45.0 mmol, 0.5 equiv). The reaction mixture was
stirred for 1 h, diluted (EtOAc), washed (1.times.H.sub.2O and
1.times.brine), dried (Na.sub.2SO.sub.4), and concentrated under
reduced pressure. Flash chromatography of the residue (SiO.sub.2,
20-25% EtOAc/Hexane, gradient elution) provided the product as a
yellow solid.
(b) 2-(4-Aminophenyl)-1,1,1-trifluoropropan-2-ol (i). A solution of
1,1,1-trifluoro-2-(4-nitrophenyl)propan-2-ol prepared as in step
(a) (19.5 g, 82.9 mmol, 1.0 equiv) in EtOH (300 mL) was treated
with SnCl.sub.2 (78.6 g, 415 mmol, 5.0 equiv). After stirring at
70.degree. C. for 2 h, the reaction mixture was concentrated under
reduced pressure, diluted (EtOAc) and washed (3.times.1 N aqueous
NaOH and 1.times.brine). The organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the product as a yellow solid.
(c) 1,1,1-Trifluoro-2-[4-(isopropylamino)phenyl]propan-2-ol (ii). A
solution of 2-(4-aminophenyl)-1,1,1-trifluoropropan-2-ol prepared
above in step (b) (8.80 g, 42.9 mmol, 1.0 equiv) and acetone (15.7
mL, 215 mmol, 5.0 equiv) in CH.sub.3CN (90 mL) was treated at
0.degree. C. with NaBH.sub.3CN (13.5 g, 215 mmol, 5.0 equiv). The
reaction was stirred for 10 min at 0.degree. C., treated with AcOH
(8.1 mL, 141 mmol, 3.3 equiv) and stirred for 2 h at 25.degree. C.
The reaction mixture was treated again with AcOH (8.1 mL, 141 mmol,
3.3 equiv) and stirred for 28 h. The reaction was quenched (1 M
aqueous NaOH), extracted (EtOAc), dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. Flash chromatography of the
residue (SiO.sub.2, 5-10% MeOH/CH.sub.2Cl.sub.2 containing 1% of
28% NH.sub.3 in H.sub.2O, gradient elution) afforded the product as
a yellow foam.
(d)
N-Isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzene-
sulfonamide (1). A solution of
1,1,1-trifluoro-2-[4-(isopropylamino)phenyl]propan-2-ol prepared
above in step (c) (40 mg, 0.16 mmol, 1.0 equiv) and benzenesulfonyl
chloride (30 mg, 0.16 mmol, 1.0 equiv) in CH.sub.2Cl.sub.2 (1.0 mL)
was treated with pyridine (39 .mu.L, 0.48 mmol, 3.0 equiv). After
stirring at 25.degree. C. for 2 days, the reaction was diluted
(EtOAc) and washed (1.times.1 M aqueous HCl, 1.times.saturated
NaHCO.sub.3, and 1.times.brine). The organics were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. Flash
chromatography of the residue (SiO.sub.2, 20% EtOAc/Hexane) gave
the product as a pale yellow solid. .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 7.75 (d, J=8.4 Hz, 2H), 7.56-7.46 (m, 5H), 7.07 (d,
J=8.4 Hz, 2H), 4.63-4.57 (m, 1H), 2.37 (s, 1H), 1.79 (s, 3H), 1.05
(d, J=6.7 Hz, 3H), 1.04 (d, J=6.7 Hz, 3H). MS (ESI) 388
[M+H].sup.+.
Example 2
Preparation of
2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]be-
nzenesulfonamide (2)
##STR00045##
Following steps (a), (b), (c), and (d) described above in Example
1, but substituting 2-chlorobenzenesulfonyl chloride for
benzenesulfonyl chloride in step (d),
2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]be-
nzenesulfonamide (2) was prepared. The racemic product was resolved
by chiral HPLC to give optical isomers 2a and 2b. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.82 (dd, J=1.5, 7.9 Hz, 1H),
7.54-7.43 (m, 4H), 7.25-7.23 (m, 1H) 7.12 (d, J=8.6 Hz, 2H),
4.78-4.70 (m, 1H), 2.36 (s, 1H), 1.75 (s, 3H), 1.16 (d, J=6.7 Hz,
3H), 1.15 (d, J=6.7 Hz, 3H). MS (ESI) 422 [M+H].sup.+. The flow
rate was 18 mL/min on a Chiralpak AD-H 20 mm I.D..times.250 mm, 5
mic column (Daicel Chemical Industries LTD), using 5% isopropyl
alcohol/hexane as the eluent. Complete resolution was achieved at
up to 30 mg racemate per injection.
Example 3
Preparation of
2,3-dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pheny-
l]benzenesulfonamide (3)
##STR00046##
Following steps (a), (b), (c), and (d) described above in Example
1, but substituting 2,3-dichlorobenzenesulfonyl chloride for
benzenesulfonyl chloride in step (d),
2,3-dichloro-N-isopropyl-N-[4-(1,1,1
-trifluoro-2-hydroxypropan-2-yl)phenyl]benzenesulfonamide (3) was
prepared. The racemic product was resolved by chiral HPLC to give
optical isomers 3a and 3b. .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 7.76 (dd, J=1.4, 8.0 Hz, 1H), 7.62 (dd, J=1.4, 8.0 Hz, 1H),
7.50 (d, J=8.5 Hz, 2H), 7.18 (dd, J=8.0, 8.0 Hz, 1H), 7.10 (d,
J=8.5 Hz, 2H), 4.79-4.73 (m, 1H), 2.35 (s, 1H), 1.76 (s, 3H), 1.17
(d, J=6.7 Hz, 3H), 1.16 (d, J=6.7 Hz, 3H). MS (ESI) 456
[M+H].sup.+. The flow rate was 10 mL/min on a Chiralpak AS-H 20 mm
I.D..times.250 mm, 5 mic column (Daicel Chemical Industries LTD),
using 10% isopropyl alcohol/hexane as the eluent. Complete
resolution was achieved at up to 30 mg racemate per injection.
Example 4
Preparation of
2-fluoro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]be-
nzenesulfonamide (4)
##STR00047##
Following steps (a), (b), (c), and (d) described above in Example
1, but substituting 2-fluorobenzenesulfonyl chloride for
benzenesulfonyl chloride in step (d),
2-fluoro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]be-
nzenesulfonamide (4) was prepared. .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 7.75-7.71 (m, 1H), 7.59-7.55 (m, 1H), 7.55 (d,
J.dbd.8.5 Hz, 2H), 7.27-7.19 (m, 2H), 7.12 (d, J=8.5 Hz, 2H),
4.78-4.72 (m, 1H), 2.40 (s, 1H), 1.80 (s, 3H), 1.16 (d, J=6.7 Hz,
3H), 1.15 (d, J=6.7 Hz, 3H). MS (ESI) 406 [M+H].sup.+.
Example 5
Preparation of
2,6-dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pheny-
l]benzenesulfonamide (5)
##STR00048##
Following steps (a), (b), (c), and (d) described above in Example
1, but substituting 2,6-dichlorobenzenesulfonyl chloride for
benzenesulfonyl chloride in step (d),
2,6-dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pheny-
l]benzenesulfonamide (5) was prepared. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.52 (d, J=8.4 Hz, 2H), 7.39-7.36 (m, 2H), 7.29-7.26
(m, 1H), 7.15 (d, J=8.4 Hz, 2H), 4.85-4.78 (m, 1H), 2.37 (s, 1H),
1.77 (s, 3H), 1.18 (d, J=6.7 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H). MS
(ESI) 456 [M+H].sup.+.
Example 6
Preparation of
2-chloro-4-cyano-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (6)
##STR00049##
Following steps (a), (b), (c), and (d) described above in Example
1, but substituting 2-chloro-4-cyanobenzenesulfonyl chloride for
benzenesulfonyl chloride in step (d),
2-chloro-4-cyano-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (6) was prepared. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.91 (d, J.dbd.8.2 Hz, 1H), 7.83 (d, J=1.4 Hz,
1H), 7.53 (dd, J=1.4, 8.2 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H) 7.05 (d,
J=8.4 Hz, 2H), 4.83-4.76 (m, 1H), 2.36 (s, 1H), 1.77 (s, 3H), 1.18
(d, J=6.7 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H). MS (ESI) 447
[M+H].sup.+.
Example 7
Preparation of
2,5-dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pheny-
l]benzenesulfonamide (7)
##STR00050##
(a)
2,5-Dichloro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzen-
esulfonamide. A solution of
2-(4-aminophenyl)-1,1,1-trifluoropropan-2-ol (i) prepared above in
step (b) in Example 1 (1.00 g, 4.87 mmol, 1.0 equiv) and
2,5-dichlorobenzenesulfonyl chloride (1.21 g, 4.87 mmol, 1.0 equiv)
in CH.sub.2Cl.sub.2 (20 mL) was treated with pyridine (1.18 mL,
14.6 mmol, 3.0 equiv). After stirring for 1.5 h, the solution was
diluted (EtOAc) and washed (1.times.1 M aqueous HCl,
1.times.saturated aqueous NaHCO.sub.3, and 1.times.brine). The
organics were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Flash chromatography of the residue (SiO.sub.2,
30% EtOAc/Hexane) gave the product as a yellow solid.
(b)
2,5-Dichloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (7). A solution of
2,5-dichloro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzenesul-
fonamide prepared above in step (a) (103 mg, 0.25 mmol, 1.0 equiv.)
in DMF (2.0 mL) was treated with isopropyl iodide (250 .mu.L, 2.50
mmol, 10 equiv.) and K.sub.2CO.sub.3 (346 mg, 2.50 mmol, 10 equiv).
After stirring at 75.degree. C. for 1 h, the solution was diluted
(EtOAc) and washed (3.times.brine). The organics were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. Flash
chromatography of the residue (SiO.sub.2, 25% EtOAc/Hexane) gave
the product 7 as a pale yellow solid.
(c) The racemic product was resolved by chiral HPLC to give optical
isomers 7a and 7b. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.82
(d, J=2.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.48-7.39 (m, 2H), 7.11
(d, J=8.4 Hz, 2H), 4.75-4.68 (m, 1H), 2.37 (s, 1H), 1.77 (s, 3H),
1.16 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.7 Hz, 3H). MS (ESI) 456
[M+H].sup.+. The flow rate was 18 mL/min on a Chiralpak AS-H 20 mm
I.D..times.250 mm, 5 mic column (Daicel Chemical Industries LTD),
using 7% isopropyl alcohol/hexane as the eluent. Complete
resolution was achieved at up to 30 mg racemate per injection
Example 8
Preparation of
N-tert-butyl-2,5-dichloro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen-
yl]benzenesulfonamide (8)
##STR00051##
Following step (b) described above in Example 7, but substituting
tert-butyl bromide for isopropyl iodide,
N-tert-butyl-2,5-dichloro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen-
yl]benzenesulfonamide (8) was prepared. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.71 (d, J=2.4 Hz, 1H), 7.48-7.42 (m, 2H),
7.37-7.26 (m, 4H), 2.40(s, 1H), 1.74 (s, 3H), 1.48 (s, 9H). MS
(ESI) 470 [M+H].sup.+.
Example 9
Preparation of
2-chloro-N-(cyclopropylmethyl)-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl-
)phenyl]benzenesulfonamide (9)
##STR00052##
Following steps (a) and(b) described above in Example 7, but
substituting 2-chlorobenzenesulfonyl chloride for
2,5-dichlorobenzenesulfonyl chloride in step (a) and
(bromomethyl)cyclopropane for isopropyl iodide in step (b),
2-chloro-N-(cyclopropylmethyl)-N-[4-(1,1,1-trifluoro-2-hydroxypropan-
-2-yl)phenyl]benzenesulfonamide (9) was prepared. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.83 (dd, J=1.6, 8.0 Hz, 1H),
7.54-7.40 (m, 4H), 7.29-7.26 (m, 2H), 7.24-7.21 (m, 1H), 3.71 (d,
J=7.1 Hz, 2H), 2.35 (s, 1H), 1.74 (s, 3H), 1.02-0.90 (m, 1H),
0.48-0.43 (m, 2H), 0.18-0.13 (m, 2H). MS (ESI) 434 [M+H].sup.+.
Example 10
Preparation of
2,5-dichloro-N-isobutyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl-
]benzenesulfonamide (10)
##STR00053##
Following step (b) described above in Example 7, but substituting
1-bromo-2-methylpropane for isopropyl iodide,
2,5-dichloro-N-isobutyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl-
]benzenesulfonamide (10) was prepared. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.78 (d, J=2.3 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H),
7.39-7.37 (m, 2H), 7.26 (d, J=8.6 Hz, 2H), 3.66 (d, J=7.4 Hz, 2H),
2.33 (s, 1H), 1.75 (s, 3H), 1.70-1.62 (m, 1H), 0.95 (d, J=6.6 Hz,
3H), 0.95 (d, J=6.6 Hz, 3H). MS (ESI) 470 [M+H].sup.+.
Example 11
Preparation of
2-chloro-N-isopropyl-5-nitro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (11)
##STR00054##
Following steps (a) and (b) described above in Example 7, but
substituting 2-chloro-5-nitrobenzenesulfonyl chloride for
2,5-dichlorobenzenesulfonyl chloride in step (a),
2-chloro-N-isopropyl-5-nitro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (11) was prepared. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.66 (d, J=2.7 Hz, 1H), 8.29 (dd,
J=2.7, 8.7 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H),
7.10 (d, J=8.4 Hz, 2H), 4.80-4.73 (m, 1H), 2.35 (s, 1H), 1.77 (s,
3H), 1.19 (d, J=6.4 Hz, 3H), 1.18 (d, J=6.4 Hz, 3H). MS (ESI) 467
[M+H].sup.+.
Example 12
Preparation of
5-amino-2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (12)
##STR00055##
A solution of
2-chloro-N-isopropyl-5-nitro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (11) (704 mg, 1.50 mmol, 1.0 equiv) in
EtOH (40 mL) was treated with SnCl.sub.2.2H.sub.2O (1.70 g, 7.50
mmol, 5.0 equiv). After stirring at 75.degree. C. for 2 h, the
reaction mixture was concentrated under reduced pressure, diluted
(EtOAc) and washed (3.times.1 M aqueous NaOH and 1.times.brine).
The organics were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Flash chromatography of the residue (SiO.sub.2,
30-40% EtOAc/Hexane, gradient elution) gave the product as a white
foam. .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 7.59 (d, J=8.6
Hz, 2H), 7.28 (d, J=8.6 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.08 (d,
J=2.8 Hz, 1H), 6.73 (dd, J=2.8, 8.6 Hz, 1H), 6.65 (s, 1H), 5.67 (s,
1H), 4.50-4.42 (m, 1H), 1.67 (s, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.03
(d, J=6.6 Hz, 3H). MS (ESI) 437 [M+H].sup.+.
Example 13
Preparation of
5-bromo-2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (13)
##STR00056##
A solution of
5-amino-2-chloro-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)p-
henyl]benzenesulfonamide (12) (287 mg, 0.66 mmol, 1.0 equiv) and
CuBr.sub.2 (294 mg, 1.32 mmol, 2.0 equiv) in CH.sub.3CN (6.0 mL)
was treated with isoamyl nitirite (180 .mu.L, 1.32 mmol, 2.0 equiv)
at 0.degree. C. After stirring at 25.degree. C. for 1 h, the
solution was diluted (EtOAc) and washed (3.times.brine). The
organics were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Flash chromatography of the residue (SiO.sub.2,
20% EtOAc/Hexane) gave the product as a white solid. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.96 (d, J=2.3 Hz, 1H), 7.57 (dd,
J=2.3, 8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 1H),
7.12 (d, J=8.5 Hz, 2H), 4.79-4.70 (m, 1H), 2.37 (s, 1H), 1.77 (s,
3H), 1.16 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.7 Hz, 3H). MS (ESI) 500
[M+H].sup.+.
Example 14
Preparation of
2-chloro-N-ethyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzen-
esulfonamide (14)
##STR00057##
(a) tert-Butyl
4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylcarbamate. A solution
of 2-(4-aminophenyl)-1,1,1-trifluoropropan-2-ol (i) prepared above
in step (b) in Example 1 (13.8 g, 67.3 mmol, 1.0 equiv) in THF (100
mL) was treated with NaOH (33.5 mL, 2.0 M in H.sub.2O, 1.0 equiv)
and Boc.sub.2O (14.6 g, 67.3 mmol, 1.0 equiv) at 0.degree. C. and
heated to 40.degree. C. After stirring for 12 h, the reaction was
cooled to 25.degree. C., diluted (saturated aqueous NaHCO.sub.3),
extracted (3.times.EtOAc) and washed (1.times.brine). The organics
were dried (MgSO.sub.4) and concentrated under reduced pressure.
Flash chromatography of the residue (SiO.sub.2, 5%
MeOH/CH.sub.2Cl.sub.2) gave the product as a white solid.
(b) tert-Butyl
ethyl[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]carbamate. A
solution of tert-butyl
4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenylcarbamate prepared
above in step (a) (500 mg, 1.64 mmol, 1.0 equiv) in DMF (5.0 mL)
was treated at 0.degree. C. with NaH (138 mg, 60% in mineral oil,
3.44 mmol, 2.1 equiv). The reaction was stirred for 20 min at
0.degree. C. and ethyl bromide (138 .mu.L, 1.80 mmol, 1.1 equiv)
was added. After stirring for 50 min at 25.degree. C., the reaction
was diluted (EtOAc), washed (3.times.brine), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure. Flash
chromatography of the residue (SiO.sub.2, 15% EtOAc/Hexane)
provided the product as a pale yellow foam.
(c) 2-(4-(Ethylamino)phenyl)-1,1,1-trifluoropropan-2-ol. A sample
of tert-butyl
ethyl[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]carbamate
prepared above in step (b) (182 mg, 0.55 mmol, 1.0 equiv) was
treated with trifluoroacetic acid (2.1 mL, 27.5 mmol, 50 equiv) and
the mixture was stirred at 25.degree. C. for 20 min. The volatiles
were removed under a stream of N.sub.2 and the residue was diluted
(EtOAc) and washed (1.times.saturated aqueous NaHCO.sub.3 and
1.times.brine). The organics were dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure to provide the product as a
yellow solid.
(d)
2-Chloro-N-ethyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]be-
nzenesulfonamide (14). A solution of
2-(4-(ethylamino)phenyl)-1,1,1-trifluoropropan-2-ol prepared above
in step (c) (40 mg, 0.17 mmol, 1.0 equiv) and
2-chlorobenzenesulfonyl chloride (37 mg, 0.17 mmol, 1.0 equiv) in
CH.sub.2Cl.sub.2 (1.0 mL) was treated with pyridine (42 .mu.L, 0.51
mmol, 3.0 equiv). After stirring at 25.degree. C. for 12 h, the
solution was diluted (EtOAc) and washed (1.times.1 N aqueous HCl,
1.times.saturated aqueous NaHCO.sub.3, and 1.times.brine). The
organics were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Flash chromatography of the residue (SiO.sub.2,
20% EtOAc/Hexane) gave the product as a white solid. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.83 (dd, J=1.5, 7.9 Hz, 1H),
7.52-7.47 (m, 3H), 7.45-7.42 (m, 1H), 7.27-7.25 (m, 1H), 7.24-7.21
(m, 2H), 3.88 (q, J=7.1 Hz, 2H), 2.36 (s, 1H), 1.74 (s, 3H), 1.15
(t, J=7.1 Hz, 3H). MS (ESI) 408 [M+H].sup.+.
Example 15
Preparation of
2-chloro-N-methyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benze-
nesulfonamide (15)
##STR00058##
Following steps (b), (c), and (d) described above in Example 14,
but substituting methyl iodide for ethyl bromide in step (b),
2-chloro-N-methyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benze-
nesulfonamide (15) was prepared. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 7.91 (dd, J=1.5, 8.3 Hz, 1H), 7.54-7.43 (m, 4H), 7.34-7.29
(m, 1H), 7.24-7.21 (m, 2H), 3.41 (s, 3H), 2.32 (s, 1H), 1.75 (s,
3H). MS (ESI) 394 [M+H].sup.+.
Example 16
Preparation of
2-chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N-is-
opropylbenzenesulfonamide (16)
##STR00059##
(a) 2-(4-Amino-3-chlorophenyl)-1,1,1-trifluoropropan-2-ol. A 100 mL
flask was charged with 410 mg
2-(4-aminophenyl)-1,1,1-trifluoropropan-2-ol (i) (2.0 mmol, 1.0
equiv), 267 mg N-chlorosuccinimide (2.0 mmol, 1.0 equiv) and 3 mL
acetonitrile. The flask was equipped with a reflux condenser, and
placed into a preheated 85.degree. C. bath with stirring for 3 h.
The solution was diluted with H.sub.2O, extracted (10%
MeOH/CH.sub.2Cl.sub.2), washed (brine), dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. Flash chromatography of
the residue (SiO.sub.2, 5% MeOH/CH.sub.2Cl.sub.2) provided the
product as a white solid.
(b)
2-Chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)b-
enzenesulfonamide.
2-(4-Amino-3-chlorophenyl)-1,1,1-trifluoropropan-2-ol (95.6 mg, 0.4
mmol, 1.0 equiv) was combined in a flask with 84.4 mg
2-chlorosulfonyl chloride (0.4 mmol, 1.0 equiv), 0.5 mL pyridine
and 0.5 mL acetone, and the reaction mixture was refluxed for 4 h.
The solution was cooled, diluted with H.sub.2O, extracted (EtOAc),
washed (brine), dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Flash chromatography of the residue (SiO.sub.2,
2% MeOH/CH.sub.2Cl.sub.2) gave the product as a white solid.
(c)
2-Chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)--
N-isopropylbenzenesulfonamide (16). To a suspension of 15 mg
2-chloro-N-(2-chloro-4-(1,1,1,-trifluoro-2-hydroxypropan-2-yl)phenyl)benz-
enesulfonamide (0.036 mmol, 1.0 equiv), 40 mg K.sub.2CO.sub.3 (0.29
mmol, 8.0 equiv) and 0.5 mL DMF was added 123 mg isopropyl iodide
(0.73 mmol, 20.0 equiv). The resulting suspension was heated to
120.degree. C. with stirring for 1 h, the suspension was diluted
with sat. NaHCO.sub.3, extracted (CH.sub.2Cl.sub.2), washed
(brine), dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Flash chromatography of the residue (SiO.sub.2, 1%
MeOH/CH.sub.2Cl.sub.2) gave the product (16) as a white solid.
.sup.1HNMR (CDCl.sub.3, 500 MHz) .delta. 7.84 (dd, J=8.0, 1.5 Hz, 1
H), 7.66 (s, 0.5 H), 7.60 (s, 0.5 H), 7.56-7.48 (m, 3 H), 7.42 (dd,
J=7.5, 3.5 Hz, 1 H), 7.29 (dd, J=7.5, 7.5 Hz, 1 H), 4.9 (m, 1 H),
2.46 (s, 1 H), 1.78 (s, 3 H), 1.27 (dd, J=5.0, 5.0 Hz, 3H), 1.18
(dd,J=7.5, 7.5 Hz, 3 H). MS (ESI) 456.0 (M+H.sup.+).
Example 17
Synthesis of
2-chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N-et-
hylbenzenesulfonamide (17)
##STR00060##
Using the methods described in Example 16 above, substituting ethyl
bromide for isopropyl iodide,
2-chloro-N-(2-chloro-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N-et-
hylbenzenesulfonamide (17) was prepared. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.82 (dd, J=8.0, 1.5 Hz, 1 H), 7.61 (s, 1 H), 7.53
(d, J=7.5 Hz, 1 H), 7.48-7.45 (m, 2 H), 7.41 (d, J=8.5 1 H), 7.28
(dd, J=8.5, 8.5 Hz, 1 H), 4.0 (m, 2 H), 2.80 (s, 1 H), 1.78 (s, 3
H), 1.19 (dd, J=7.5, 7.5 Hz, 3 H). MS (ESI) 442.0 (M+H.sup.+).
Example 18
Synthesis of
2-chloro-N-(1-fluoropropan-2-yl)-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2--
yl)phenyl)benzenesulfonamide (18)
##STR00061##
(a)
1,1,1-Trifluoro-2-(4-(1-fluoropropan-2-ylamino)phenyl)propan-2-ol.
To a 100 mL flask charged with 820 mg
2-(4-aminophenyl)-1,1,1-trifluoropropan-2-ol (i) (4.0 mmol, 1.0
equiv), 1.44 mL AcOH and 20 mL acetonitrile were added 1.52 g
fluoroacetone (20.0 mmol, 5.0 equiv) and 1.24 g NaCNBH.sub.3 (20.0
mmol, 5 equiv). After stirring for 2 h at room temperature, the
solution was diluted with 1 N NaOH, extracted (EtOAc), washed
(brine), dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Flash chromatography of the residue (SiO.sub.2,
CH.sub.2Cl.sub.2) provided the product as a white solid.
(b)
2-Chloro-N-(1-fluoropropan-2-yl)-N-(4-(1,1,1-trifluoro-2-hydroxypropa-
n-2-yl)phenyl)benzenesulfonamide (18).
1,1,1-Trifluoro-2-(4-(1-fluoropropan-2-ylamino)phenyl)propan-2-ol
(53 mg, 0.2 mmol, 1.0 equiv) was combined in a flask with 126.7 mg
2-chlorosulfonyl chloride (0.6 mmol, 3.0 equiv) and 1.0 mL
pyridine, and the reaction mixture was refluxed for 2 h. The
solution was diluted with H.sub.2O, extracted (EtOAc), washed
(brine), dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Flash chromatography of the residue (SiO.sub.2, 30%
EtOAc/Hexane) gave the product (18) as a light yellow solid.
.sup.1HNMR (CDCl.sub.3, 500 MHz) .delta. 7.82 (dd, J=8.0, 1.5 Hz, 1
H), 7.56 (d, J=8.0 Hz 1H), 7.53 (d, J=7.5 Hz, 2 H), 7.48 (ddd,
J=8.5, 8.5, 1.5 Hz, 1 H), 7.28 (dd, J=8.5, 8.5 Hz, 1 H), 7.16 (dd,
J=8.5, 1.5 Hz, 2 H), 4.9 (m, 1 H), 4.34-4.13 (m, 2 H), 2.49 (s, 1
H), 1.77 (s, 3 H), 1.16 (d, J=8.5 Hz, 3 H). MS (ESI) 440.2
(M+H.sup.+).
Example 19
Preparation of
2,5-dichloro-N-(2,2,2-trifluoroethyl)-N-[4-(1,1,1-trifluoro-2-hydroxyprop-
an-2-yl)phenyl]benzenesulfonamide (19)
##STR00062##
A mixture of
2,5-dichloro-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)benzenesul-
fonamide (7) (prepared as in Example 7, 60.0 mg, 0.146 mmol),
K.sub.2CO.sub.3 (161.5 mg, 1.17 mmol) and
CF.sub.3CH.sub.2OSO.sub.2CCl.sub.3 (204 mg, 0.723 mmol) in DMF (1.0
mL) was stirred at 110.degree. C. for 18 h. The reaction mixture
was cooled to room temperature, diluted with Et.sub.2O (10 mL). The
solution was washed with water and brine, dried, and concentrated.
Flash chromatography of the residue, using 3:7 EtOAc-Hexane, gave
2,5-dichloro-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N-(2,2,2--
trifluoroethyl)benzenesulfonamide (19). .sup.1H NMR (CDCl.sub.3)
.delta. 7.73(s, 1H), 7.51(d, J=8.0 Hz, 2 H), 7.45(d, J=8.4 Hz, 1
H), 7.41(d, J=8.4 Hz, 1 H), .delta. 7.27(d, J=8.0 Hz, 2 H), 4.48(m,
2 H), 2.50(s, 1H), 1.73(s, 3 H). MS (ESI) 496.3 (M+H.sup.+).
Example 20
Preparation of
2,3-dichloro-N-(2,2,2-trifluoroethyl)-N-[4-(1,1,1-trifluoro-2-hydroxyprop-
an-2-yl)phenyl]benzenesulfonamide (20)
##STR00063##
A mixture of
2,3-dichloro-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)benzenesul-
fonamide (3) (prepared as in Example 6, 32.0 mg, 0.077 mmol),
K.sub.2CO.sub.3 (86 mg, 0.62 mmol) and CF.sub.3CH.sub.2OSO.sub.2
CCl.sub.3 (109 mg, 0.385 mmol) in DMF (1.0 mL) was stirred at
110.degree. C. for 18 h. The reaction mixture was cooled to room
temperature, diluted with Et.sub.2O (10 mL). The solution was
washed with water and brine, dried, and concentrated. Flash
chromatography of the residue, using 3:7 EtOAc-Hexane, gave 2,3
-dichloro-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N-(2,2,2-tri-
fluoroethyl)benzenesulfonamide (20). .sup.1H NMR (CDCl.sub.3)
.delta. 7.70(dd, J=8.0, 1.6 Hz, 1 H), 7.61(dd, J=8.0, 1.6 Hz, 1 H),
7.48(d, J=8.0 Hz, 2H), 7.27(d, J=8.0 Hz, 2 H), .delta. 7.15(dd,
J=8.0, 8.0 Hz, 1 H), 4.52(m, 2 H), 2.43(br, 1H), 1.72(s, 3 H). MS
(ESI) 496.2 (M+H.sup.+).
Example 21
Preparation of
2-chloro-N-(2,2,2-trifluoroethyl)-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-
-yl)phenyl]benzenesulfonamide (21)
##STR00064##
A mixture of
2-chloro-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)benzenesulfona-
mide (2) (prepared as in Example 7, 48.4 mg, 0.128 mmol),
K.sub.2CO.sub.3 (141.3 mg, 1.02 mmol) and
CF.sub.3CH.sub.2OSO.sub.2CCl.sub.3 (181 mg, 0.64 mmol) in DMF (1.0
mL) was stirred at 110.degree. C. for 18 h. The reaction mixture
was cooled to room temperature, diluted with Et.sub.2O (10 mL). The
solution was washed with water and brine, dried, and concentrated.
Flash chromatography of the residue, using 3:7 EtOAc-hexane, gave
2-chloro-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N-(2,2,2-trif-
luoroethyl)benzenesulfonamide 21. .sup.1H NMR (CDCl.sub.3) .delta.
7.77(dd, J=8.0, 1.0 Hz, 1 H), 7.54(d, J=8.0 Hz, 1 H), 7.52-7.43(m,
3 H), 7.29(d, J=8.0, 2 H), .delta. 7.23(dd, J=8.0, 8.0 Hz, 1 H),
4.55(m, 2 H), 2.57(br, 1H), 1.74(s, 3 H). MS (ESI) 462.2
(M+H.sup.+).
Example 22
Preparation of
2,3-dichloro-N-cyclopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phe-
nyl]benzenesulfonamide (22)
##STR00065##
(a) Preparation of an aryl halide intermediate. To
4'-bromoacetophenone (10 g, 50 mmol) in THF (80 mL) cooled to
0.degree. C. was added TMSCF.sub.3 (11 mL, 75 mmol). Over a period
of 5 min, 1 M TBAF in THF (0.38 mL) was added drop wise to the
solution. After 30 min., the cooling source was removed and the
solution was stirred for 2.5 h. The solvent was removed by rotary
evaporation. The residue was dissolved in CH.sub.2Cl.sub.2 (200 mL)
and extracted against water (200 mL). The partitioned organics were
dried with Na.sub.2SO.sub.4. Following removal of the
CH.sub.2Cl.sub.2 by rotary evaporation, the residue was distilled
(78-82.degree. C., 0.1 mm Hg) to yield the bromide.
##STR00066##
(b) General procedure for Pd catalyzed amination of aryl halides.
To an argon purged sealed tube containing Pd.sub.2(dba).sub.3 (0.27
g, 0.30 mmol), (.+-.)-BINAP (0.56 g, 0.90 mmol), and NaOtBu (1.4 g,
14 mmol) was added degassed toluene (10 mL). Cyclopropylamine (0.84
mL, 12 mmol), bromide iii (prepared as above, 4.4 g, 10 mmol), and
toluene (10 mL) were combined under argon in a separate vial and
added to the catalyst suspension under argon. The tube was sealed
under argon and heated in an 80.degree. C. oil bath for 16 h. The
cooled reaction suspension was diluted with CH.sub.2Cl.sub.2 (200
mL) and extracted against water (100 mL). The organics were dried
with Na.sub.2SO.sub.4 and removed in vacuo. Silica gel column
chromatography (elution with 5% ethyl acetate in hexanes) afforded
alkyl aniline iv.
##STR00067##
(c)
2,3-Dichloro-N-cyclopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl-
)phenyl]benzenesulfonamide (22). To cyclopropyl aniline iv prepared
above (0.10 g, 0.32 mmol) and 2,3-dichlorobenzenesulfonyl chloride
(0.093 g, 0.38 mmol) was added pyridine (0.5 mL). The solution was
heated to 100.degree. C. for a period of 30 min, diluted with
H.sub.2O (5 mL) and acidified (pH 1) with 1 M HCl. Following
extraction of the resulting mixture with CH.sub.2Cl.sub.2
(2.times.1 mL), the collected organics were added to 1 M TBAF in
THF (2 mL) and the resulting solution was extracted with H.sub.2O
(2 mL). Partitioned organics were dried with Na.sub.2SO.sub.4, and
concentrated in vacuo. Silica-gel column chromatography (eluting
with 15% ethyl acetate in hexanes) afforded 22. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 0.70-0.90 (m, 4H), 1.79 (s, 3H), 2.37
(bs, 1H), 2.9-3.0 (m, 1H), 7.29 (m 1 H), 7.31 (d, J=9 Hz, 2H), 7.53
(d, J=9 Hz, 2H), 7.68 (d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H).
Example 23
Preparation of
2,5-dichloro-N-cyclobutyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen-
yl]benzenesulfonamide (23)
##STR00068##
To a solution of the cyclobutyl aniline prepared according to the
general procedure for the preparation of cyclopropyl aniline iv
(0.082 mg, 0.25 mmol) in CHCl.sub.3 (0.25 mL) was added pyridine
(0.040 mL, 0.50 mmol) followed by the portion wise addition of
2,5-dichlorobenzenesulfonyl chloride (0.073 mg, 0.30 mmol). The
reaction was stirred at room temperature for 20 h. To the reaction
was added a solution of 1 M TBAF in THF (0.25 mL). The organics
were washed with 2.5 M HCl (0.5 mL), dried with Na.sub.2SO.sub.4,
and concentrated in vacuo. Silica gel column chromatography
(gradient of 10 to 30% ethyl acetate in hexanes) afforded 23.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.45-1.65 (m, 2H), 1.79
(s, 3H), 1.85-1.95 (m, 2 H), 2.15-2.25 (m, 2H), 2.45 (s, 1H),
4.87-4.95 (m, 1H), 7.08 (d, J=8.8 Hz, 2 H), 7.4-7.5 (m, 2 H), 7.56
(d, J=8.4 Hz, 2 H), 7.78 (s, 1H).
Example 24
Preparation of
2,5-dichloro-N-phenyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]b-
enzenesulfonamide (24)
##STR00069##
(a) To an argon purged tube sealed with a rubber septum and
containing Pd.sub.2(dba).sub.3 (0.055 g, 0.060 mmol) and
(.+-.)-BINAP (0.110 g, 0.18 mmol) was added toluene (2 mL). The
solution was stirred for 10 min. under argon at room temperature.
To the solution was added the bromide prepared above (0.89 g, 2.0
mmol) and aniline (0.219 mL, 2.4 mmol). The seal was removed and
Cs.sub.2CO.sub.3 (0.92 g, 2.8 mmol) was added followed by addition
of toluene (2 mL). The tube was purged with argon and sealed with a
Teflon stopper. The reaction mixture was heated to 100.degree. C.
for 20 h. After cooling, H.sub.2O (5 mL) was added to the reaction,
and the resulting suspension was extracted with ethyl acetate
(2.times.5 mL). Combined organics were dried with MgSO.sub.4,
concentrated in vacuo, and purified by silica gel chromatography
(eluting with 5% ethyl acetate in hexanes) to afford the
diphenylaniline.
(b)
2,5-Dichloro-N-phenyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen-
yl]benzenesulfonamide (24). To the diphenylaniline prepared above
(0.050 g, 0.141 mmol) in CHCl.sub.3 (0.15 mL) and pyridine (0.023
mL, 0.28 mmol) was added portion wise 2,5-dichlorobenzenesulfonyl
chloride. The reaction was stirred at room temperature for 5 h. To
the reaction was added 1 M TBAF in THF (0.5 mL) followed by
H.sub.2O (2 mL). The suspension was extracted with CH.sub.2Cl.sub.2
(2.times.2 mL). The organics were dried with Na.sub.2SO.sub.4,
concentrated in vacuo, and purified by silica gel chromatography
(gradient 5-20% ethyl acetate in hexanes) to afford 24. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.77 (s, 3H), 2.37 (s, 1H), 7.30-7.38
(m, 5 H), 7.42 (d, J=8.9 Hz, 2 H), 7.47-7.5 (m, 2H), 7.55 (d, J=9
Hz, 2 H), 7.93-7.97 (m, 1 H).
Example 25
Preparation of
2-cyclopropyl-N-isopropyl-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phen-
yl]benzenesulfonamide (25)
##STR00070##
To a vessel containing
2-bromo-N-isopropyl-N-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)ben-
zenesulfonamide (ii) (prepared as in Example 1, 0.020 g, 0.043
mmol), cyclopropylboronic acid (0.0070 g, 0.086 mmol),
K.sub.3PO.sub.4 (0.018 g, 0.086 mmol), and Pd(PPh.sub.3).sub.4
(0.0050 mg, 0.0043 mmol) under nitrogen atmosphere was added
degassed toluene (0.40 mL) and H.sub.2O (0.040 mL). The vessel was
sealed under nitrogen atmosphere and heated in a 95.degree. C. oil
bath for 17.5 h. The reaction was cooled to room temperature,
diluted with CH.sub.2Cl.sub.2 (2 mL), and extracted with H.sub.2O
(1 mL). The combined organics were dried with Na.sub.2SO.sub.4,
concentrated in vacuo, and purified by silica gel chromatography
(gradient elution 5-20% ethyl acetate in hexanes) to afford 25.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.85-0.090 (m, 2H),
1.10-1.19 (m, 8H), 1.78 (s, 3 H), 2.42 (bs, 1 H), 2.70-2.80 (m, 1
H), 4.53 (septet, J=6.7, 1H), 6.86 (d, J=7.8 Hz, 1H), 7.14 (t,
J=7.3, 1H), 7.21 (d, J=8.6, 2H), 7.41 (t, J=7 Hz, 1 H), 7.53 (d,
J=8.4 Hz, 2H), 7.84 (d, J=8 Hz, 1H).
Biological Examples
Procedures Useful for the Biological Evaluation of the Aniline
Sulfonamide Derivatives
In addition to the extensive literature disclosing the role of HSDs
in various diseases and disorders, described herein are assays
useful for testing the aniline sulfonamide derivatives of the
present invention.
Assays
In vitro 11.beta.-HSD1 (Hydroxysteroid Dehydrogenase 1) Activity
Inhibitory Action
The 11.beta.-HSD1 inhibitory activity was examined by quantitative
determination by an SPA (scintillation proximity assay) system of
the suppressive action on the conversion from cortisone to cortisol
using human 11.beta.-HSD1 (hereinafter recombinant 11.beta.-HSD1)
expressed using a baculo-virus system as an enzyme source. For the
reaction, a reagent was added to a 96 well plate (96 well
Opti-plates.TM.-96 (Packard)) to the following final concentration
and a volume of 100 .mu.l was reacted at room temperature for 90
min. The reaction solution used was 0.1 .mu.g/ml recombinant
11.beta.-HSD1, 500 .mu.M NADPH, 16 nM .sup.3H cortisone (Amersham
Biosciences, 1.78 Tbq/mol) dissolved in 0.1% BSA (Sigma)-containing
PBS and the test drug was 2 .mu.l of a compound solution (dissolved
in DMSO). After 90 min, the reaction was stopped by adding PBS (40
.mu.l, containing 0.1% BSA (Sigma)) containing 0.08 .mu.g of
anti-cortisol mouse monoclonal antibody (East Coast Biologics), 365
.mu.g SPA PVT mouse antibody-binding beads (Amersham Biosciences)
and 175 .mu.M carbenoxolone (Sigma) to the reaction solution. After
the completion of the reaction, the plate was incubated overnight
at room temperature and the radioactivity was measured by Topcount
(Packard). For control, the value (0% inhibition) of the well
containing 2 .mu.l of DMSO instead of the test drug was used, and
for positive control, the value (100% inhibition) of the well
containing carbenoxolone instead of the test drug at the final
concentration of 50 .mu.M was used. The inhibition (%) of the test
drug was calculated by ((value of control-value of test
drug)/(value of control-value of positive control)).times.100 (%).
The IC.sub.50 value was analyzed using a computer-based curve
fitting soft.
This following example provides assays that are useful in
evaluating and selecting a compound that modulates
11.beta.-HSD1.
Biochemical 11.beta.-HSD1 assay by SPA
Recombinant human, mouse and rat 11.beta.-HSD1 were expressed in
baculovirus expression system, isolated by affinity purification
and used as the enzyme sources for cortisone to cortisol conversion
in vitro. .sup.3H-Cortisone (Amersham Bioscience, 1.78 Tbq/mol. 49
Ci/mmol) was used as the substrate, and a monoclonal anti-cortisol
antibody and the scintillation proximity assay (SPA) system were
used to detect the product of the 11.beta.-HSD1-catalyzed reaction,
.sup.3H-cortisol. Reactions took place at room temperature for 90
min. in 96-well Opti-plates.TM.-96 (Packard) in 100 .mu.L volume
with 2 .mu.L test compounds or control in DMSO, 0.1 .mu.g/mL
11.beta.-HSD1 protein, 500 .mu.M NADPH and 16 nM radioactive
cortisone, in PBS buffer supplemented with 0.1% BSA (Sigma).
Reaction was stopped with the addition of 40 .mu.L buffer
containing 0.08 .mu.g anti-cortisol monoclonal antibody (East Coast
Biologics), 365 .mu.g SPA PVT antibody-binding beads (Amersham
Biosciences) and 175 .mu.M carbenoxolone (Sigma).
Plates were incubated at room temperature overnight before being
read on a Topcount (Packard). The point of 50% inhibition of
11.beta.-HSD1 enzyme activity (IC.sub.50) was determined by
computer-based curve fitting.
Cell-based 11.beta.-HSD1 Assay by SPA
This cell-based assay measures the conversion of .sup.3H-cortisone
to .sup.3H-cortisol in a HEK-293 cell line stably overexpressing
human recombinant 11.beta.-HSD1. HEK-293 cells were grown in
DMEM/F12 supplemented with 10% fetal bovine serum, and plated onto
poly-D-lysine-coated 96-well assay plates (Costar 3903), 100,000
cells per well in 50 .mu.L assay media (phenol free DMEM/F12
(Invitrogen) +0.2% BSA+1% antibiotic-antimycotic solutions). The
solution was incubated at 37.degree. C. for 24 h, and the reaction
was initiated by the addition of 25 .mu.L of assay media containing
compounds of desired concentration and 25 .mu.L of assay media
containing 40 nM of .sup.3H-cortisone to each well. The reaction
mixture was incubated at 37.degree. C. for 90 min. and the reaction
terminated by the addition of 25 .mu.L of assay media containing
0.2 .mu.g of anti-cortisol monoclonal antibody (East Coast
Biologics), 500 .mu.g SPA PVT antibody-binding beads (Amersham
Biosciences) and 500 .mu.M carbenoxolone (Sigma).
Plates were incubated at room temperature for at least 2 h before
being read on Topcount (Packard). The point of 50% inhibition of
11.beta.-HSD1 enzyme activity (IC.sub.50) was determined by
computer-based curve fitting.
The compounds prepared in the foregoing examples exhibited
11.beta.-HSD1 enzyme activity (IC.sub.50) in the assays ranging
from <1 nM to 1000 nM.
* * * * *
References